Part 2 book “Essentials of clinical immunology” has contents: Joints and muscles, skin diseases, eye diseases, chest diseases, gastrointestinal and liver diseases, endocrinology and diabetes, haematological diseases, neuroimmunology, pregnancy, techniques in clinical immunology,… and other contents.
CHAPTER 10 10 Joints and Muscles 10.1 Introduction, 178 10.2 Patterns of joint disease, 178 10.3 Arthritis and infection, 179 10.3.1 Septic arthritis, 179 10.4 Rheumatoid arthritis, 180 10.4.1 Diagnosis, 180 10.4.2 Serology, 180 10.4.3 Pathology, 181 10.4.4 Immunopathogenesis, 182 10.4.5 Aetiology, 183 10.4.6 Outcome, 184 10.4.7 Management, 185 10.5 Seronegative spondyloarthritis, 185 10.5.1 Ankylosing spondylitis, 185 10.5.2 Other seronegative spondyloarthritides, 186 10.5.3 Other seronegative arthritides, 187 10.6 Chronic arthritis in children, 188 10.7 Systemic lupus erythematosus, 189 10.8 10.9 10.10 10.11 10.7.1 Clinical features, 189 10.7.2 Laboratory findings, 190 10.7.3 Differential diagnosis, 191 10.7.4 Drug-induced systemic lupus erythematosus, 191 10.7.5 Management, 191 10.7.6 Prognosis, 192 10.7.7 Aetiology and pathogenesis, 193 Other connective tissue diseases, 195 10.8.1 Mixed connective tissue disease, 195 10.8.2 Sjögren’s syndrome, 196 10.8.3 Scleroderma, 197 Systemic vasculitis, 197 10.9.1 Polyarteritis nodosa, 197 10.9.2 Polymyalgia rheumatica and giant cell (temporal) arteritis, 198 10.9.3 Other vasculitides, 199 Inflammatory muscle disease or myositis, 199 Hereditary periodic fevers, 200 10.1 Introduction 10.2 Patterns of joint disease Immunological mechanisms are responsible for many rheumatological diseases Although these disorders often present with joint or muscle inflammation, many have multisystem involvement with a particular tendency to involve skin, lungs and kidney These disorders, which include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), dermatomyositis, scleroderma and some forms of vasculitis, are often referred to as the ‘connective tissue diseases’; this woolly phrase is rather meaningless in pathophysiological terms, but remains in widespread use Because of the multisystem involvement, discussion of these disorders can also be found in other organ-based chapters The connective tissue diseases are characteristically associated with non-organ-specific autoantibody production, particularly against components of cell nuclei These autoantibodies are not necessarily responsible for joint or tissue damage, but are often helpful in diagnosis or prognosis (see Chapter 19) Joint diseases fall into two broad categories: degenerative conditions of cartilage (osteoarthritis) or disorders characterized by inflammation of the joint lining or synovium (inflammatory arthritis or synovitis) The diagnosis of a particular form of inflammatory arthritis is only rarely made using a single diagnostic test; notable exceptions being the presence in synovial fluid of uric acid crystals in gout or of bacteria in septic arthritis Instead, the diagnostic process usually relies heavily upon clinical assessment, with a smaller role being played by various immunological tests (Table 10.1) Most forms of chronic inflammatory joint diseases can be defined using clinical criteria alone, and this, in part, reflects our ignorance of the underlying aetiopathogenesis The major common patterns of joint inflammation and the common underlying causes are summarized in Table 10.2 The healthy synovial lining (Fig 10.1) consists of a single layer of cells overlying loose, well-vascularized stromal tissue The lining cells are of two kinds: one fibroblastic, which 178 1405127619_4_010.indd 178 01/03/2006 16:50:12 JOINTS AND MUSCLES Table 10.1 Major factors in the assessment of the patient with joint disease Age/sex Acute or chronic? Pattern of joint disease? Monoarticular Oligoarticular Polyarticular Extra-articular disease? Rheumatoid factor positive? Antinuclear antibody positive? Table 10.2 Common patterns of inflammatory joint disease Pattern of joint inflammation Common causes Monoarthritis Bacterial infection Gout/pseudogout Spondyloarthropathy (especially reactive arthritis) Oligoarthritis Spondyloarthritis (especially reactive and psoriatic) Gout/pseudogout Polyarthritis Symmetrical Asymmetrical Rheumatoid arthritis Systemic lupus erythematosus Viral arthritis Psoriatic arthritis Normal Rheumatoid arthritis Synovial lining Cartilage Macrophages Plasma cells Infiltration Lymphocytes (T cells) New blood vessel formation Pannus Thickened synovial lining Synovial fluid containing: immune complexes complement breakdown products and enzymes Capsule Polymorphonuclear leucocyte Fig 10.1 Diagrammatic representation of a joint One side is normal, the other shows characteristic pathological features of rheumatoid arthritis 1405127619_4_010.indd 179 179 synthesizes the proteoglycans, which act as a lubricant within the joint, and one derived from macrophages, which probably have a scavenging function Unlike most body surfaces, free passage of intercellular fluid can occur across the synovial membrane, a factor which may explain why antigens tend to be deposited within the joint The synovial response to injury is relatively limited, and the pathology of most forms of inflammatory arthritis consists of hyperplasia of the lining layer and cellular infiltration of the vascular tissues beneath the lining Cytokine production in chronic synovial inflammation may also be limited in its variety: most synovial diseases show some response to treatments which block the action of tumour necrosis factor (TNF)-α 10.3 Arthritis and infection There are two principal mechanisms whereby microorganisms can cause inflammatory arthritis: direct invasion of the synovium (infective or septic arthritis) or a hypersensitivity response (mediated by T-cell or immune complexes) against microbial antigen deposited within the joint 10.3.1 Septic arthritis Pyogenic arthritis can occur in previously healthy joints in immunocompetent subjects, but the risk is greatly increased by previous joint damage or defective immunity, particularly abnormalities of antibody production or neutrophils (the latter being most often a consequence of therapy) Joint damage probably increases the risk of sepsis by allowing increased entry of organisms into the joint Patients with RA have a particular propensity to joint sepsis, this being partly due to corticosteroid therapy and joint damage, but also related to subtle defects in immunity associated with the disease itself (Case 10.1) The organisms most frequently associated with septic arthritis are summarized in Table 10.3 Septic arthritis is a medical emergency Delay in treatment is associated with an increasing risk of severe joint damage and with high mortality in immunocompromised subjects Table 10.3 Relative frequency of bacterial causes of septic arthritis in the UK Staphylococcus aureus Pneumococcus Other streptococci Haemophilus influenzae Gram-negative bacilli Gonococcus* 40% 10% 18% 7% 12% < 1% *Gonococcal joint infection is much more common in North America and Australia 01/03/2006 16:50:36 180 CHAPTER 10 CASE 10.1 SEPTIC ARTHRITIS A 37-year-old woman developed a symmetrical polyarthritis A test for rheumatoid factor was positive and erosive changes were seen on X-ray, confirming a clinical diagnosis of RA The arthritis followed an aggressive course with poor response to a variety of disease-modifying antirheumatic drugs and she became increasingly disabled due to severe destructive changes in the knees, wrists and shoulders A moderate dose of prednisolone was introduced at the age of 42, with some symptomatic improvement in her joints and she was referred to an orthopaedic surgeon with a view to knee replacements However, month before her orthopaedic appointment she presented to the emergency department with a painful swollen right knee On examination she was unwell, febrile (38 °C) and had a hot, red right knee with a sizable effusion Eighty millilitres of purulent synovial fluid was aspirated from the joint and microscopy of the fluid revealed numerous Gram-positive cocci A diagnosis of septic arthritis was made on a background of severe RA and steroid therapy She was treated with high-dose antibiotics and the joint was washed out via an arthroscope Culture of blood and synovial fluid grew Staphylococcus aureus She received weeks’ antibiotic treatment in total together with vigorous physiotherapy Her knee, however, was significantly worsened by the infection and she could no longer straighten the leg or walk more than a few yards Joint replacement was deferred for months to reduce the risk of infection in the prosthesis Gonococcal and meningococcal infection can be associated with arthritis This is most often associated with a subacute septicaemic illness, and organisms can be isolated from the blood and synovial fluid However, in meningococcal infection, an immune complex-mediated arthropathy can also occur, which usually presents 7–10 days after the onset of infection and is associated with falling levels of meningococcal antigen in serum, rising levels of antibody and evidence of complement consumption, all features suggesting an immune complex-mediated disease Lyme disease, which is caused by the tick-borne spirochaete Borrelia burgdorferi, is associated with a chronic largejoint arthritis This first appears some months after the initial tick bite, and usually has a relapsing and remitting course, but can be persistent and associated with joint destruction Organisms are difficult to isolate from the joint, but an antibody response can be detected The arthritis may be partly mediated by hypersensitivity mechanisms but improves after antibiotic treatment, suggesting that live organisms play a role in pathogenesis Immune-mediated arthritis The distinction between active infection and immune-mediated arthritis is not always clear-cut, as the above account makes clear There are other forms of arthritis which appear to be triggered by infection and which follow a subacute, relapsing or chronic course The most common of these, reactive arthritis, is discussed further in section 10.5 It will also be apparent from the sections on RA, other spondyloarthritides and juvenile chronic arthritis, that attempts have been made to explain most forms of chronic inflammatory joint disease in terms of inappropriate response to an unidentified organism This model has perhaps been most successfully applied to the spondyloarthritides (see section 10.5) Other disorders in which arthritis is immune mediated include rheumatic fever, which is discussed in Chapter 2, and Henoch–Schönlein purpura, discussed in Chapter Viral arthritis Joint and muscle pain is very common in acute viral infections, but inflammatory arthritis is much less common Infections such as rubella, mumps and hepatitis B can cause a transient arthritis which is probably due to a combination of direct infection and hypersensitivity This can also occur after immunization with attenuated but live rubella virus The most common viral cause of arthritis in adults is parvovirus B19 (which in children usually only produces a mild febrile illness with a characteristic ‘slapped cheek’ rash) This produces a symmetrical, peripheral polyarthritis (clinically similar to early RA), which usually remits within weeks but which can occasionally persist for several months RA is a common disease affecting 1–2% of the adult population and is twice as common in women as men It is most common between the ages of 25 and 55 years, and the most frequent presentation is an insidious, symmetrical polyarthritis, although the disease can begin abruptly Although systemic manifestations may be present at the outset, they develop more usually as the disease progresses (Table 10.4 and Case 10.3) The diagnosis of RA is made on clinical grounds, as illustrated in Case 10.2 1405127619_4_010.indd 180 10.4 Rheumatoid arthritis 10.4.1 Diagnosis 10.4.2 Serology There is no diagnostic test for RA Patients with RA fall into two groups: those with usually less severe disease who 01/03/2006 16:50:36 JOINTS AND MUSCLES 181 CASE 10.2 RHEUMATOID ARTHRITIS A 37-year-old woman gradually developed painful wrists over months; she consulted her doctor only when the pain and early morning stiffness stopped her from gardening On examination, both wrists and the metacarpophalangeal joints of both hands were swollen and tender but not deformed (see Fig 10.2) There were no nodules or vasculitic lesions On investigation, she was found to have a raised C-reactive protein (CRP) level (27 mg/l) (NR < 10) but a normal haemoglobin and white cell count A latex test for rheumatoid factor was negative and antinuclear antibodies were not detected The clinical diagnosis was early RA and she was treated with ibuprofen Despite some initial symptomatic improvement, the pain, stiffness and swelling of the hands persisted and month later both knees became similarly affected She was referred to a rheumatologist She was seen months after the initial presentation By this time she was struggling to work, drive and carry heavy objects A test for rheumatoid factor was now positive (titre 1/256) X-rays of the feet showed small but definite erosions in two metatarsal heads She still had a raised CRP (43 mg/l) but normal serum complement (C3 and C4) levels This woman had rheumatoid arthritis with some features suggesting a poor prognosis Her treatment was changed to weekly low-dose methotrexate This has controlled the arthritis for several years and no further erosions have developed Table 10.4 Extra-articular features of rheumatoid arthritis: the commonest features are marked in bold (adapted from Bacon) lack circulating rheumatoid factor (seronegative RA); and a larger group (70%) with more aggressive disease who have, or develop, a rheumatoid factor in the serum (seropositive RA) Extra-articular disease occurs predominantly in this seropositive group Rheumatoid factor is of more value in prognosis than in diagnosis Rheumatoid factor, in this context, refers only to the IgM antibody which binds aggregated IgG as its antigen (see Chapter 19) Rheumatoid factors of the IgG or IgA class are not clinically helpful, although may play a role in joint inflammation Antibodies to citrullinated peptides (anti-CCP antibodies—see section 10.4.4) seem to have high specificity for the diagnosis of RA, and their presence predicts a poorer prognosis However, anti-CCP antibody testing is not yet in widespread clinical use Other serological tests are of little value in RA Antinuclear antibody (ANA) is present in 40%, but is usually of low titre and often of IgM class; such ANAs are found in many other conditions Serum complement C3 and C4 levels may be normal or raised due to an ‘acute-phase’ reaction (see Chapter 1) CRP (another ‘acute-phase’ reactant) is also raised, particularly in active RA; this helps to distinguish active RA from active SLE (see Fig 10.8) Intrinsic or essential systemic features of rheumatoid disease Rheumatoid nodules Serositis (pleurisy, pericarditis) Vasculitis Neuropathy (often caused by vasculitic damage to nerves) Felty’s syndrome (neutropenia and splenomegaly) Consequences of chronic inflammation and immune stimulation Anaemia Weight loss and fever Lymphadenopathy Complications of rheumatoid disease Entrapment neuropathy, e.g carpal tunnel syndrome Accelerated atherosclerosis Infection Amyloidosis Cervical myelopathy Complications of treatment Osteoporosis (corticosteroids) Accelerated atherosclerosis Infection Drug-specific side-effects Associated syndromes (also occur without RA) Keratoconjunctivitis sicca Interstitial lung diseases Episcleritis and scleritis 1405127619_4_010.indd 181 Fig 10.2 Symmetrical synovitis in early rheumatoid arthritis With permission from Medical Masterclass: Rheumatology and Clinical Immunology, London: Royal College of Physicians, 2001 10.4.3 Pathology The earliest pathological change in RA appears to be an infiltrate of neutrophils and mononuclear cells around small blood vessels in the loose connective tissue beneath the syn- 01/03/2006 16:50:42 182 CHAPTER 10 ovium As the disease progresses, large numbers of T cells, macrophages, B cells and plasma cells accumulate in this tissue and the synovium becomes markedly thickened due to fibroblast proliferation and macrophage migration The surface area increases and becomes folded into villi New vessel formation occurs and some blood vessels develop into structures specialized for lymphocyte migration: so-called high endothelial venules (see section 1.7) Secondary lymphoid follicles also develop In consequence, the histological structure comes to resemble that of an activated lymph node, emphasizing the high degree of immunological activity in RA Large amounts of synovial fluid can form (especially in large joints), and this contains large numbers of neutrophil polymorphs, which have migrated from the blood This chronic inflammatory tissue has several destructive effects upon the joint First, the hypertrophied lining layer at the margins of the joint (known as pannus) erodes cartilage and underlying bone Second, cytokines induce chondrocytes and fibroblasts to produce enzymes which break down the extracellular matrix Third, degranulation of neutrophils in the synovial fluid can directly damage the surface of cartilage (Fig 10.1) 10.4.4 Immunopathogenesis The immunohistology of rheumatoid synovium suggests that the disease results from an immunological response to an antigen within the joint The nature of this immunological response and the target antigen remain uncertain It is, however, clear that joint destruction in RA is driven by activated macrophages (Fig 10.3), which mediate tissue breakdown directly and also activate other cells in the joint A large number of inflammatory mediators are produced in RA synovium (Fig 10.3), and early descriptions of cytokine production in RA talked of a ‘cytokine soup’, with many different pathways leading to joint damage (and by implication no simple way of inhibiting this process) Some pattern has emerged from this apparent inflammatory chaos with the demonstration that TNF-α, largely derived from macrophages, plays a central role in this inflammatory process (Fig 10.4): inhibition of this cytokine with neutralizing antibodies reduces the production of most other inflammatory mediators in cell culture When these antibodies are administered to patients, a dramatic improvement in joint inflammation occurs The members of the interleukin (IL)-1 family, IL-1α and IL-1β, also play an important role, although less crucial than TNF There is probably more than one immunological mechanism leading to macrophage activation in rheumatoid synovium The most widely accepted model is a process driven by CD4+ T cells The evidence for T-cell involvement in RA is summarized in Table 10.5 However, the model of RA as a 1405127619_4_010.indd 182 Unknown antigen CD4+ T cell Small immune complexes (e.g RF and IgG) Acute phase responses IL-6 Fibroblasts Further cell recruitment γ Interferon TNF GM-CSF IL-6, TNF, IL-1 Chemokines TNF, IL-1 Endothelial cells Macrophage TNF IL-1 TNF IL-1 Chondrocytes Growth factors Breakdown of extracellular matrix by proteolytic enzymes Fig 10.3 How CD4+ T cells and immune complexes may control the events leading to joint damage in rheumatoid arthritis Induces production of proinflammatory cytokines e.g IL-1, IL-6, chemokines Stimulates and activates endothelial cells, leading to further recruitment of cells within the joint TNFα Stimulates cells within joint to break down the matrix which surrounds them Stimulates macrophages to produce matrix metallo-proteinases and free radicals Fig 10.4 The central role of tumour necrosis factor (TNF)-α in controlling rheumatoid synovial inflammation T-cell-driven disease has been criticized, as T-cell cytokines such as IL-2 and interferon (IFN)-γ are hard to detect in RA synovium, in contrast to macrophage-derived cytokines such as TNF-α, IL-1 and IL-6, which are present in abundance Therapies specifically directed at T cells have also been only partially successful in controlling the disease Inflammation driven by antibodies may also be important Models of RA pathogenesis from the 1960s and 1970s focused on inflammation driven by complement activation induced by immune complexes containing rheumatoid factors and IgG Rheumatoid factor and other autoantibodies were relegated to a minor subsidiary role with the rise of T-cell models of RA synovitis in the 1980s and 1990s However, the recent clinical demonstration that depletion of B cells (with an anti-CD20 monoclonal antibody, rituximab—see Chapter 7) dramatically improves the clinical features of RA, suggests that antibody-mediated inflammation may after all play a crucial role in the disease (Table 10.5) There is some evidence that 01/03/2006 16:51:00 JOINTS AND MUSCLES Table 10.5 Evidence that T and B cells play a central role in the pathogenesis of rheumatoid arthritis (RA) T cells • Rheumatoid synovium densely infiltrated with mature T cells (mainly CD4+) bearing activation markers • Disease closely associated with particular MHC class II polymorphism, i.e DR4 • Therapy directed against T cells (e.g cyclosporin) modestly effective in treatment • RA improves with progression of HIV infection • Most animal models critically dependent upon T cells B cells • Rheumatoid synovium contains large numbers of plasma cells • Disease closely associated with autoantibodies: rheumatoid factor and anti-citrullinated peptide antibodies • Efficacy of therapy specifically directed against B cells (rituximab) • B cells also important in animal models small immune complexes can directly activate macrophages via Fc receptors If RA is an immunologically mediated disease, then it should be possible to define the main antigens driving the T- and B-cell responses in the joint These antigens could be self-molecules expressed in the joint or could be foreign (e.g bacterial or viral) antigens sequestered in joint tissue T- and B-cell responses to a number of autoantigens have been described in RA (Table 10.6), but most are not specific for RA and the role of responses against these antigens in the disease is unclear One of the most plausible autoimmune models of RA would be for the disease to be driven by an immune response against an antigen whose expression is confined to joints, such as type II collagen, the main protein of articular cartilage However, although immune responses against cartilage and synovial proteins can be found in some patients with RA, these are not found in all and are also found in other diseases Antibodies against a number of peptides containing the unusual amino acid, citrulline (anti-CCP antibodies) 183 have recently been found to be highly specific to RA and to predict aggressive and persistent disease The antigen-driving production of these antibodies, and their role in disease, awaits clarification Plausible but unproven models of synovial inflammation driven by self-perpetuating rheumatoid factor production have also been proposed There is also evidence that macrophage-induced inflammation can become self-sustaining and independent of any triggering immune response: cytokines such as TNF-α produced by macrophages induce further macrophage activation It is plausible that different mechanisms may predominate at different stages of this chronic disease, with immune mechanisms being key in earlier disease 10.4.5 Aetiology In Europeans there is an association between possession of HLA-DR4 and -DR1 and rheumatoid factor-positive RA This association becomes stronger with increasing severity of disease, and the presence of extra-articular manifestations Different associations were described in other ethnic groups and a common link to the DR4/DR1 association was not apparent until the detailed structure of DR molecules became known at the amino acid level This allowed comparison of different DR alleles associated with RA Almost all alleles associated with RA (HLA-DRB1∗0101, 0401 and 0404) have a distinctive five amino acid sequence near the peptide-binding region of the DRβ chain; this sequence is known as the ‘shared epitope’ Possession of two copies of the ‘shared epitope’ (one inherited from each parent) is associated with a high risk of severe disease (Table 10.7) Other genes also appear to be important in determining susceptibility to RA, but the shared epitope association seems to be the strongest Female sex is an important genetic risk factor, and it seems plausible that this risk is mediated hormonally Environmental factors predisposing to RA remain poorly understood Smoking is a weak risk factor, and use of the oral contraceptive may protect against RA There is an increased risk of onset of RA in the post-partum period Many attempts have been made to link RA to infectious agents such as parvovirus, Epstein–Barr virus, mycoplasma and myco- Table 10.6 Autoimmune responses identified in patients with rheumatoid arthritis (RA) 1405127619_4_010.indd 183 Autoantigen Antibodies in RA T cell response in RA Specificity for RA IgG Type II collagen and other cartilage antigens Citrullinated proteins (CCP) Yes: rheumatoid factor Yes: in 10–20% Yes Yes: in 10–20% Probably No No Yes 01/03/2006 16:51:00 184 CHAPTER 10 Table 10.7 How possession of an HLA-DRB1 allele containing the ‘shared epitope’ influences absolute risk of developing rheumatoid arthritis (RA) in a Caucasian population The risk is highest in those who inherit a copy of a different DRB1 gene from each of their parents Data from Nepom G Rheum Dis Clin N Am 1992; 18:785 Approximate risk of developing RA Total population Subjects with no copies of shared epitope DRB1*0401 DRB1*0404 DRB1*0101 DRB1*0401 and 0404 in 100 in 580 in 35 in 20 in 80 in bacteria However, while the idea of RA as a disease either initiated or perpetuated by an immune response against an infection has many attractions, no convincing evidence exists to implicate any known agent (see Chapter for discussion of how infections may trigger autoimmunity) Many animal models of RA have been developed, centred on both infection and autoimmunity, all with some similarity to the human disease If nothing else, these models emphasize that the synovial response to injury is limited in scope and most of the above aetiological factors are plausible 10.4.6 Outcome Although the outcome of RA is variable and some patients have mild or remitting disease, it is for most a severe and disabling illness Most (70%) of RA patients have many periods of remission and relapse over decades (polycyclic disease) A small proportion (15%) are fortunate to have monocyclic disease and recover over a few years without relapse Progressive RA, with relentless increase in disability with few partial remissions, occurs in another 15% Joint damage begins in the early stages of the disease and once established is effectively irreversible Five years after diagnosis, one-third of patients are unable to work at all and only one-third are still in full-time work At 10 years, 10– 20% of those affected are highly dependent upon others for self-care Factors predicting a poor prognosis are detailed in Table 10.8 It is now also apparent that RA is associated with increased mortality as well as disability Life expectancy in RA is reduced by approximately years compared with age- and sexmatched controls In severe, disabling RA, the 5-year mortality is around 50% The causes of these premature deaths are multiple and often not directly attributable to the arthritis, although some patients die of extra-articular disease (Case 10.3) such as vasculitis, amyloid (see Chapter 9) or the sideeffects of drug treatment Patients with RA also show an increased susceptibility to severe or recurrent infection, in both those treated with steroids and those who have not received steroids The largest single contributor to increased mortality in RA is, however, an increased risk of ischaemic CASE 10.3 PULMONARY FIBROSIS IN RHEUMATOID ARTHRITIS A 61-year-old man, with a 15-year history of seropositive RA, was admitted with increasing shortness of breath, myalgia and weight loss He had previously smoked 40 cigarettes a day but had never been exposed to coal or silica dust On examination, he was pale and thin, with generalized muscle tenderness Widespread crepitations were heard over both lung fields His joints were tender and he had subluxation of the metacarpophalangeal joints of both hands There was bilateral cervical and axillary lymph node enlargement but no splenomegaly Neurological and cardiac examinations were normal Investigations showed a raised CRP (81 mg/l) and a normochromic anaemia (Hb 95 g/l) but a normal white cell count His serum IgG was raised at 44 g/l (NR 7.2–19.0), although IgA and IgM levels were normal He had a strongly positive rheumatoid factor titre of 1/1280 (NR < 1/32) There were no detectable antibodies to DNA or to extractable nuclear antigens (ENA) (see Chapter 1405127619_4_010.indd 184 19) and the serum levels of muscle enzymes were normal A chest X-ray suggested pulmonary fibrosis High-resolution computed tomographic scanning of the chest confirmed severe pulmonary fibrosis, with no evidence of any ground glass shadowing (a feature suggesting response to immunosuppression) Pulmonary function tests showed a severe restrictive defect, with an forced expiratory volume in sec/forced expiratory vital capacity of 1.1/1.3 He was too unwell to undergo a lung biopsy This man’s dyspnoea was rapidly progressive and he continued to deteriorate despite intravenous corticosteroids and cyclophosphamide At autopsy, both lungs showed severe fibrosis, with the pattern of usual interstitial pneumonia (see section 13.4.3), which is a rare complication of RA with a poor prognosis The onset of serious complications of RA so long after the initial diagnosis is not unusual 01/03/2006 16:51:00 JOINTS AND MUSCLES Table 10.8 Predictors of a poor prognosis in early rheumatoid arthritis High titre serum rheumatoid factor Female sex High levels of acute phase proteins (ESR, CRP) High levels of disability Extra-articular disease Radiological evidence of joint damage Serum anti-citrullated peptide (anti-CCP) antibodies Possession of the shared epitope: two copies are worse than one ESR, Erythrocyte sedimentation rate; CRP, C-reactive protein heart disease (IHD) Mortality from IHD in RA is increased by approximately two- to three-fold, a comparable increase in risk to that seen in diabetes mellitus Similar increased mortality from IHD has also been described in other chronic inflammatory diseases, particularly SLE The mechanisms underlying this increased risk are unclear, but conventional risk factors alone (such as smoking, hyperlipidaemia and hypertension) cannot explain the increased risk, and corticosteroid treatment and disease-specific factors make substantial contributions 10.4.7 Management Although management of RA is a multidisciplinary process, aiming to control the disease and minimize pain and disability, the paramount aim of treatment is the pharmacological limitation of joint inflammation and damage Joint damage in RA begins early, is effectively irreversible and has a poor outcome: these are compelling reasons to introduce effective, aggressive treatment early in the disease Recognition of these factors has led to an increasing tendency for early use of disease-modifying drugs, particularly in subjects felt to have a poor prognosis Methotrexate, leflunomide and sulphasalazine (Chapter 7) are the most commonly used drugs There is an increasing tendency to use drugs in combination in severe or aggressive disease; these combinations are more effective and no more toxic than single drug regimes Corticosteroids are widely used, usually being administered directly into inflamed joints, since systemic use can be associated with severe side-effects on longterm use Patients who fail treatment with methotrexate and similar drugs are now usually treated with anti-TNF agents, such as etanercept and infliximab, which can control RA in 60–70% of patients refractory to other treatments Anti-TNF agents may have advantages over conventional drugs in early disease, but their use is currently limited by their high cost It is notable that 30–40% of patients show little or no response to anti-TNF agents, suggesting that inflammatory 1405127619_4_010.indd 185 185 mechanisms that are not critically dependent on TNF-α are operating in these patients Small numbers of patients have been treated with highly aggressive chemotherapy and autologous stem cell transplantation with some success (see section 8.5.6), but the long-term utility of this approach is not yet clear Dramatic responses in patients with refractory disease have been reported following treatment with the anti-B-cell monoclonal antibody, rituximab Recombinant IL-1 receptor antagonist (Chapter 1) has also been used to block the action of IL-1α and IL-1β, but the response is not as striking as that seen with anti-TNF agents A difficulty with selecting patients for treatment with earlier and more aggressive therapy is identification of patients with a poor prognosis In order to prevent disability and restore normal life expectancy, treatment needs to be instituted before major joint damage has occurred However, RA is a very variable disease and even with a combination of genetic, serological and clinical markers (Table 10.8), selection of patients with a poor prognosis is currently imperfect 10.5 Seronegative spondyloarthritis This group of disorders includes ankylosing spondylitis, Reiter’s syndrome and reactive arthritis, psoriatic arthropathy and enteropathic arthritis These syndromes are characterized by absence of rheumatoid factor (seronegative), spinal (spondylo-) involvement and often asymmetrical peripheral arthritis, tending to involve large joints Inflammation at the insertion of muscles, ligaments or tendons into bone, or enthesitis, is a core feature in these disorders It has been recognized for many years that enthesitis underlies the spinal involvement Recent studies of early joint inflammation in spondyloarthropathies using magnetic resonance imaging (MRI) or ultrasound imaging have demonstrated that synovial inflammation also begins with enthesitis at the joint margins Ossification can occur at the site of enthesitis, and in the spine this can lead to fusion (ankylosis) of adjacent vertebrae All of these disorders are strongly associated with HLA-B27, the association being strongest in subjects with predominantly spinal disease Most of these disorders show a therapeutic response to anti-TNF agents The use of the label ‘reactive arthritis’ requires comment: while any arthritic process triggered by infection could be reasonably called reactive, the diagnostic label is usually reserved for a form of spondyloarthritis described in more detail below 10.5.1 Ankylosing spondylitis Ankylosing spondylitis (AS) is a chronic inflammatory condition of the spine and sacroiliac joints It is a progressive disease in which restriction of movement is associated 01/03/2006 16:51:17 186 CHAPTER 10 CASE 10.4 ANKYLOSING SPONDYLITIS A 21-year-old man presented to his local emergency department with acute pain and swelling of one knee On examination, the joint was tender and restricted in movement X-ray of the knee showed periarticular osteoporosis On investigation, he had a raised erythrocyte sedimentation rate (ESR) of 102 mm/h, a mild anaemia (Hb 106 g/l) but no detectable serum rheumatoid factor The knee effusion was aspirated; the fluid contained a polymorphonuclear leucocytosis but no organisms or rheumatoid factor No diagnosis was made at this stage but he was treated empirically with diclofenac; his arthritis improved Fifteen months later he developed an iritis in his left eye At this point, a history was also elicited of low back pain and prolonged early morning stiffness dating back to his late teenage years His peripheral joints were normal but his lumbar spine was rigid and he had some pain and restriction of the neck X-rays of his lumbar spine and pelvis showed the classic changes of ankylosing spondylitis and tissue typing revealed that he was HLA-B27-positive (see Fig 10.5) He continues to have widespread spinal discomfort, although daily exercises have reduced the stiffness in his neck At his last clinic visit he asked whether he should receive an anti-TNF drug with ossification of the intervertebral ligaments As in Case 10.4, this disease mainly affects men aged between 15 and 30 years Four men in 1000 are affected and 5% have a positive family history Complications are common: 25% develop iritis and 20% have a peripheral arthritis, although either condition may be the sole presenting symptom Rarer complications include pulmonary fibrosis, aortic incompetence, cardiac conduction defects and amyloidosis The association between HLA-B27 and AS is very strong; over 95% of affected individuals are positive for this antigen The frequency (3–10%) of HLA-B27 in a normal, white population makes a positive test less useful in patients in whom this disease is suspected; the absence of HLA-B27 in a patient makes AS very unlikely, although it does not exclude it The precise aetiology is unknown The association of AS with HLA-B27 is shared with other arthritides which follow infection, such as Reiter’s disease (see below) Persistence of specific antigens of the infecting organisms has been demonstrated in joint tissues in these patients This suggests that AS may also be triggered by infection [possibly in the gastrointestinal (GI) tract] in susceptible HLA-B27-positive individuals The finding that two-thirds of patients with AS have asymptomatic inflammatory gut lesions supports this, although these may be caused by anti-inflammatory drugs used for therapy The relationship of arthritides and HLA-B27 remains uncertain but has been clarified by studies using transgenic 1405127619_4_010.indd 186 Fig 10.5 Bamboo lumbar spine in ankylosing spondylitis With permission from Medical Masterclass: Rheumatology and Clinical Immunology, London: Royal College of Physicians, 2001 rats The introduction of the gene for human HLA-B27 into otherwise normal rats results in a multisystem disease resembling AS The development of this disease is dependent upon exposure to gut commensal organisms, particularly Bacteroides This model confirmed that the gene is an important predisposing factor The most important aspect of treatment is exercise to maintain full mobility, with anti-inflammatory drugs to reduce the pain Joint replacement and occasionally spinal surgery may be required Anti-TNF agents are the only therapies which have been shown to have a significant effect on the spinal inflammation 10.5.2 Other seronegative spondyloarthritides Reiter’s syndrome and reactive arthritis (Case 10.5) Reiter’s syndrome and reactive arthritis can be regarded as a spectrum of disease ranging from a multisystem disorder characterized by an inflammatory arthritis, urethritis, conjunctivitis and uveitis and skin changes (Reiter’s syndrome) to disease which is confined to the joints (reactive arthritis) Of all the spondyloarthritides, the link to infection is clearest in Reiter’s/reactive arthritis: the majority of cases appear to be triggered by either sexually acquired Chlamydia trachomatis infection or by certain bacterial infections of the gut (in particular, Shigella, Salmonella, Campylobacter or Yersinia infection) The overall risk of this syndrome after a trigger- 01/03/2006 16:51:18 JOINTS AND MUSCLES 187 CASE 10.5 REITER’S DISEASE A 19-year-old man presented with acute swelling of his right knee and left ankle and extremely painful heels On questioning, he admitted to a penile discharge and dysuria for days On examination, he had bilateral Achilles tendonitis and his right knee and left ankle were red, hot and tender He had aphthous-like mouth ulcers and ulcers around the glans penis There were no skin lesions and, in particular, no evidence of keratoderma blenorrhagica or subungual pustules On investigation, he was found to have a raised ESR (60 mm/h) but a normal haemoglobin and white cell count A latex test for rheumatoid factor was negative X-rays of the joints were normal ing infection is around 1%, and HLA-B27 is an important risk factor (80% of patients are B27 positive) The syndrome is commoner in men than women (by about to 1), and tends to affect those under 40 years old Bacterial/chlamydial proteins and DNA can be detected in affected joints, but viable organisms have not been found The arthropathy results mainly from a T-cell response to the sequestered bacterial antigens Treatment is with intra-articular corticosteroid injections, anti-inflammatory drugs and physiotherapy; antibiotic treatment of the triggering infection has no effect on the arthritis Most cases remit within a few months, but around 20% (largely B27-positive patients) develop chronic peripheral joint and spinal disease Severe Reiter’s syndrome can occur in human immunodeficiency virus (HIV) infection Enteropathic arthritis Twenty percent of patients with ulcerative colitis develop a mild seronegative inflammatory arthritis, enteropathic arthritis, which affects peripheral joints Conversely, 5% of patients with ankylosing spondylitis have either clinical ulcerative colitis or Crohn’s disease Inflammatory bowel disease should be considered as an underlying cause in patients with features of a seronegative spondyloarthropathy The overlapping clinical features of HLA-B27-related arthropathies suggest that similar immunopathogenic mechanisms are involved Psoriatic arthritis Psoriasis is a common skin disease (see Chapter 11) Two percent of patients with psoriasis develop psoriatic arthropathy; this may affect the peripheral joints or the spine The psoriasis generally precedes the arthritis by many years; in rare cases where the arthritis comes first, diagnosis may be difficult A family history of psoriasis is a helpful diagnostic clue and the characteristic nail changes of psoriasis are 1405127619_4_010.indd 187 Joint fluid aspirated from the right knee showed a polymorphonuclear leucocytosis but no organisms Gonococci were not cultured from the urethral pus or from the joint fluid but chlamydial DNA was detected by the polymerase chain reaction Tissue typing showed him to be HLA-B27 positive A diagnosis of Reiter’s disease was made He was given diclofenac for symptomatic relief of the arthritis and tendonitis Four days later, he developed bilateral conjunctivitis and some photophobia However, weeks later he had fully recovered and did not relapse His chlamydial urethritis was treated with doxycycline and his partner was screened for sexually transmitted infection present in 80% of patients with psoriatic arthritis Dactylitis is a distinctive feature Treatment is similar to that for RA, including the use of anti-TNF drugs The prognosis is usually good, although severe joint destruction can occur 10.5.3 Other seronegative arthritides The disorders discussed below not share clinical and aetiological features with the spondyloarthritides but are sometimes classified with them under the loose (and largely meaningless) banner of seronegative arthritis Relapsing polychondritis is a rare, non-hereditary condition characterized by inflammation of cartilage and is often associated with arthritis Most patients have an episodic, migratory, asymmetrical polyarthritis A provisional diagnosis of seronegative RA is often made until the characteristic attacks of cartilage inflammation occur, usually in the ears, nose and trachea The aetiology of this condition is unknown Cartilage antibodies are found in some patients, and T lymphocytes sensitized to cartilage antigen have been reported in others; however, these changes may be secondary to cartilage damage rather than its cause Behỗets disease (Case 10.6) is a chronic, multisystem disorder affecting slightly more men than women Recurrent, potentially blinding, uveitis with oral and genital ulceration is the commonest clinical feature, but arthritis develops in 45% of patients and is the presenting symptom in 15% Vasculitis with thrombophlebitis and neurological involvement occurs in 25–30% of cases There is no diagnostic test and the diagnosis is entirely clinical No specific treatment is available, although corticosteroids may control symptoms and azathioprine has been shown to reduce progression of visual loss In severe cases, cyclosporin, tacrolimus and infliximab may be effective Thalidomide may be useful in refractory orogenital ulceration There is an association between Behỗets disease and HLA-B51 01/03/2006 16:51:26 MCQ Answers For detailed feedback on your answers please go to the MCQs section of our website at: www.immunologyclinic.com Cases and images are also available on our website— www.immunologyclinic.com Chapter 1 a e c ,d e b b e e d 10 b 11 e 12 c 13 c 14 e 15 b 16 d Chapter a,d,e a,d a,d True a,b,c,d,e True b,c,e True a,b,c,d,e 10 True 11 b,d,e 12 a,c 13 True 14 c,d 15 b 16 e 17 c 18 d Chapter c d e d b a c b d 10 c 11 d Chapter b,c,e a,c,e a,d a,b,c,d,e a,c,d c,d d c a,b,c,d 10 d Chapter b c d c e e Chapter d e c 344 1405127619_5_end.indd 344 28/02/2006 11:21:35 MCQ ANSWERS 10 b e a c c c b Chapter c,d,e False a,b,d True b,c,d True a,b,d,e False a,d 10 False 11 False 12 True 13 True 14 d 15 a 16 a Chapter a,e False a,c,e True a,c,d True b,c,d,e False True 10 a,c,d,e 11 d 12 a Chapter a,b,e b e a,e e c,d,e a,b,c b,c,e b 10 a,d 1405127619_5_end.indd 345 345 Chapter 10 c e c b a e c Chapter 11 d c a a c d c a Chapter 12 e d d d Chapter 13 d c b a d b e Chapter 14 b,d c c,e c a, ii; b, iii; c, i; d, ii; e, iv a,d a,b,c,e a,c,e b,c,d 10 b,d,e Chapter 15 d c a d c 28/02/2006 11:21:35 346 MCQ ANSWERS Chapter 16 d a c e b d d b d 10 a Chapter 18 d d b d e c c d e 10 e Chapter 17 e c e e d a a a e 10 e Chapter 19 b,e e,d,b,c,a b e a d a a,c d 10 d 1405127619_5_end.indd 346 28/02/2006 11:21:35 Index Note: page numbers for figures are in italics, tables in bold α-chain disease 124 abortions, recurrent 302 ABPA see allergic bronchopulmonary aspergillosis accessory mechanisms accessory molecules 9–10 functions structure acute glomerulonephritis 161–3 acute idiopathic polyneuritis see Guillain– Barré syndrome acute lymphoblastic leukaemia (ALL) microarrays 324 techniques, clinical immunology 319 acute myeloid leukaemia (AML) BMT 153 microarrays 324 adaptive immune responses antibody production 25–6 antigen processing 22, 22–3 functional basis 21–6 lymphocytes 21 T cell-mediated responses 23–5 adaptive immunity 1–2, 2, 66 effector molecules 10 ADCC see antibody-dependent cellmediated cytotoxicity Addison’s disease 272–3 adhesion molecules 9–10, 10, 14–15, 15 leucocyte–endothelial interactions 15 adjuvants 3, 138–9 autoimmunity 102 Freund’s complete adjuvant 138 MDP 138–9 adrenal disease 272–3 autoimmune 272–3 adult T-cell leukaemia/lymphoma (ATL) 117 affinity maturation, B cells 25 age influence, immunodeficiency 53 AIDS 72 see also HIV HAART 71, 76 immunopathogenesis 74–5 Kaposi’s sarcoma 71 opportunistic infection 76–7, 77 persistent generalized lymphadenopathy 72 therapeutic options 75–6 therapies, potential 74 AIHA see autoimmune haemolytic anaemias AIRE see AutoImmune REgulator airways, protective mechanisms 224 alcohol-induced liver diseases 262–3 alkylating agents, immunosuppression 127 ALL see acute lymphoblastic leukaemia allergic bronchopulmonary aspergillosis (ABPA) 231–2 allergic conjunctivitis 83, 219, 220 allergy 78–94 see also anaphylaxis allergic asthma 85, 86 allergic conjunctivitis 83 allergic rhinitis 83–5 angioedema 91–2 atopic eczema 92–4 atopy 79–80 conjunctivitis 83 contact dermatitis 94 eosinophilic infiltration 86 food allergy and intolerance 88–91, 247 genetic susceptibility 79–80, 80 hay fever 83 hyposensitization (specific allergen immunotherapy) 81 immediate hypersensitivity 78–9 inflammation 86, 87 LPR 79 mast cell triggering 79 respiratory 83–8 risk factors 78 seasonal conjunctivitis 83 skin disease 91–4 specific allergen immunotherapy (hyposensitization) 81 techniques, clinical immunology 317–18 tests 317–18 urticaria 91–2, 92 vernal conjunctivitis 83 alloantibodies, anaemias 279 allograft response, renal transplantation 147–8, 148 alloimmunization, pregnancy 304 alopecia areata 209 alums, adjuvants 139 AMA see antimitochondrial antibody AML see acute myeloid leukaemia amyloid disease 173, 173–4, 174 anaemias 275–9 see also haematological diseases AIHA 276–9 alloantibodies 279 aplastic 283 causes 275 cephalosporin-induced haemolytic anaemia 279 investigations 248 PA 244–7 pathophysiology 275 anaphylactoid reactions 82 drug-induced reaction 82 anaphylaxis 80–2 see also allergy causes 81 clinical features 80 epinephrine 80, 81, 82 latex rubber 81, 82 treatment 80, 81 wasp venom 80 ANAs see antinuclear antibodies ANCA see antineutrophil cytoplasmic antibodies anergy, autoimmunity 101–2 angioedema 91–2, 209 HAE 209 347 1405127619_6_index.indd 347 01/03/2006 15:26:17 348 INDEX ankylosing spondylitis (AS) 185–6 anti-tumour necrosis factor antibodies 130–1 antibodies 10 AIHA 276 ANCA 211 anti-tumour necrosis factor antibodies 130–1 coagulation 284 damage induction 156 functions 26–7 hormones 305 IF 246–7, 247 immunosuppression 129–31, 130 kidney diseases 156 microbial antigens, detection 312, 313 monoclonal 129, 129, 136–7, 141–2, 307, 307 neutralization 26 polyclonal 307 pregnancy 305 sperm 305 tests 54 antibody deficiency see also immunodeficiency causes 54 complications 60–1 differential diagnosis 60 infection 35–6 management 61 primary antibody deficiencies 53–61 selective or partial 58–60 symptoms 55 types 54, 55–60 antibody-dependent cell-mediated cytotoxicity (ADCC), complement system 20 antibody production adaptive immune responses 25–6 B cells 25–6 antigen-binding site antigen processing adaptive immune responses 22, 22–3 antigen-presenting cells 22, 22 APCs 22 co-stimulators 22 dendritic cells 22–3 antigen-processing cells (APCs) 22 antigen-specific IgE antibodies, RAST 317, 317–18 antigenic disguise, helminth infections 51 antigenic drift 40 antigenic modulation, protozoal infection 49 antigens immunogenicity antimitochondrial antibody (AMA), tests 307 1405127619_6_index.indd 348 antineutrophil cytoplasmic antibodies (ANCA), vasculitis 211 antinuclear antibodies (ANAs) 314–15 APA syndrome see primary antiphospholipid antibody syndrome APCs see antigen-processing cells APECED see Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dysplasia aplastic anaemia 283 apoptosis, SLE 194 arthritis see also rheumatoid arthritis chronic, children 188–9 and infection 179–80 JIA 188, 188–9 arthropathy, antibody deficiency 61 AS see ankylosing spondylitis asthma 85–8 features 86 precipitating factors 85, 87 treatment 87–8 ATL see adult T-cell leukaemia/lymphoma atopic eczema 92–4, 205 atopy, allergy 79–80 atrophic gastritis 244–7, 245 autoantibodies detection 312–17 diabetes mellitus 272 endocrine diseases 265 gastritis 247 systemic sclerosis 216 techniques, clinical immunology 312–17 autoimmune adrenal disease 272–3 autoimmune conjunctivitis 83 autoimmune disease see also autoimmunity autoimmune response 96 fungal infection 97 gene defects 99 genetic factors 104–6, 105 HLA alleles 105, 105 hypersensitivity mechanisms 107–8, 108 hypocalcaemia 97 neuromuscular junction 291–3, 292 non-organ-specific 96–7 novel approaches 142 oral tolerance 142 organ-specific 96 patterns 96–8 prevalence 97–8 self-antigens 98 T-cell vaccines 142 tissue damage 107–8 treatment 108–9, 109 viral infection 40 autoimmune enteropathy, gastrointestinal diseases 251 autoimmune haemolytic anaemias (AIHA) 276–9 antibodies 276 causes 277 cold type 277, 278–9 drug-induced 279 features 277 splenectomy 277, 278 warm antibody type 277, 277–8 autoimmune hepatitis 258–63 features 260 autoimmune liver diseases 258–63 autoimmune phenomena, antibody deficiency 61 autoimmune polyendocrine disease 274, 274 Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dysplasia (APECED) 104–5, 274 AutoImmune REgulator (AIRE) 104–5 autoimmune response autoimmune disease 96 rheumatoid arthritis 183 autoimmune skin diseases 206–9 autoimmune thyroid disease 269, 269 autoimmunity 95–109 see also autoimmune disease AIRE 104–5 anergy 101–2 B-cell tolerance 102 costimulation 101–2 defining 95–6 drugs 106–7, 107 environmental factors 106–7 Guillain–Barré syndrome 104, 294 hormones 106 infection 106 mechanisms of endocrine 264–5 molecular mimicry 104, 104 peripheral tolerance 100–2, 101, 102–3 physical agents 107 preventing 98–102 regulation 102 self-sustaining autoreactive pathogenic process 103, 103–4 self-tolerance 98–9 suppression 102 T cells 100, 100–1, 101 thymic tolerance 99–100 tolerance breakdown 102–4, 103 triggers 104–7 autoinflammatory syndromes 200, 200 B-cell antigens 54–5 B-cell lymphomas 119 01/03/2006 15:26:20 INDEX B-cell tolerance, autoimmunity 102 B cells affinity maturation 25 antibody production 25–6 clonal expansion 25 isotope switching 25 maturation 56 rheumatoid arthritis 182–3, 183 T-independent antigens 25–6 β-haemolytic streptococcal infection, complications 43 bacterial antigens, immune reactions 44 bacterial infection 41–4 bystander damage 43–4 evasion of immune defences 43, 43 immune responses, normal 41–2 streptococcal toxic shock syndrome 42 tonsillitis, acute bacterial 41 BALT see bronchial-associated lymphoid tissue Behcet’s syndrome 188, 221 benign paraproteinaemia 122–3 Berger’s disease 159–60, 160 biodegradable polymers, adjuvants 139 biopsy material, techniques, clinical immunology 316 blood transfusion 284–6 complications 285 hepatitis C 285–6 risks 285–6 BMT see bone marrow transplantation bone marrow, immune system 31 bone marrow studies, multiple myeloma 122 bone marrow transplantation (BMT) 152, 152–5, 153 AML 153 SCID 154–5 breast-feeding, immunological value 301–2 bronchial-associated lymphoid tissue (BALT) 225 bronchiectasis 57 Bruton’s disease 55–7 bullous pemphigoid 208 bullous skin diseases 206–8 Burkitt’s lymphoma 37 bystander damage bacterial infection 43–4 fungal infection 48 helminth infections 51 parasitic infection 51 protozoal infection 51 viral infection 40–1 C1 inhibitor deficiency, skin diseases 209–10, 210 C3 nephritic factor (C3 NeF), techniques, 1405127619_6_index.indd 349 clinical immunology 312 C5 convertase, complement system 19 CAH see chronic active hepatitis Campylobacter jejuni, Guillain–Barré syndrome 104 cancer see also lymphoproliferative disorders; malignancy immunosurveillance 142 immunotherapy 141–2 capsules, bacterial infection 43 cardiac disease 237–40 classification 238 endocarditis 237–8 IHD 184–5 myocarditis 237–8 pericarditis 237 rheumatic heart disease 43–4 CD1 molecules CD4+ T cells, rheumatoid arthritis 182 CD40 ligand deficiency 57, 57–8 cell-mediated immunity, parasitic infection 49, 51 cellular immune responses effector molecules 10 cephalosporin-induced haemolytic anaemia 279 cerebral malaria 48 cerebral SLE 295–6, 296 cerebrospinal fluid (CSF) MS 289, 289–90 techniques, clinical immunology 310, 310 CFS see chronic fatigue syndrome CGD see chronic granulomatous disease CHAD see cold haemagglutinin disease Chediak–Higashi syndrome 68 chemokine receptors 14 chemokines 11–14 chemotactic agents 16 chemotaxis, techniques, clinical immunology 321 chest diseases 224–40 cardiac disease 237–40 connective tissue disease and the lung 237 coronary artery disease 238–9 granulomatous diseases 227–30 interstitial lung disease 230–6 respiratory infections 225–7 chronic active hepatitis (CAH) 258–60 features 260 chronic arthritis, children 188–9 chronic fatigue syndrome (CFS) 40, 41 chronic granulomatous disease (CGD) 67–8, 68 chronic inflammatory peripheral neuropathies 294–5 349 chronic lymphatic leukaemia 226 chronic renal failure 176–7, 177 Churg–Strauss syndrome (CSS) 237 CIE see countercurrent immunoelectrophoresis circulating immune complexes, parasitic infection 51 cirrhosis see also liver diseases PBC 260–2, 261, 307 clonal expansion, B cells 25 CMV see cytomegalovirus co-stimulators, antigen processing 22, 23 co-stimulatory molecules, up-regulation 106 coagulation antibodies 284 immune disorders 283–4 coeliac disease 247–51 DH 250–1 histological features 249 Howell–Jowell bodies 248, 248 immunological features 250 inheritance 249 investigations 248 pathogenesis 250 cold haemagglutinin disease (CHAD) 278–9 cold sores 202, 203 combined primary T- and B-cell immunodeficiencies 61–5 common variable immunodeficiency disorders (CVIDs) 57–60 complement breakdown products, techniques, clinical immunology 311–12 complement components, techniques, clinical immunology 310–12, 311, 311 complement deficiency 69, 69–70, 70 SLE 193, 194 complement receptors 14 complement system 17, 17–20 activation 18, 19 ADCC 20 C5 convertase 19 control 19–20, 20 functions 17–20, 18 MBL 19 conjunctival infection 219 conjunctival sac 217, 217 conjunctivitis 218–20 allergic 83, 219, 220 autoimmune 83 hypersensitivity 218 Reiter’s syndrome 220 sarcoidosis 220 connective tissue disease and the lung 237, 237 01/03/2006 15:26:20 350 INDEX contact dermatitis 94, 203–5 agents 204 pathogenesis 205 contraceptive vaccines 305 Coombs’ tests, haematological diseases 276, 276–7 corneal grafting 152 coronary artery disease 238–9 corticosteroids immunosuppression 125–6, 126, 127 macrophages 125–6 costimulation, autoimmunity 101–2 countercurrent immunoelectrophoresis (CIE) 316, 316 Crohn’s disease 251, 251–3 aetiology 253 genetic factors 252 pathogenesis 252, 253 cryoglobulinaemia 211–13 cryoglobulins 310 cryptic epitopes 103 CSF see cerebrospinal fluid CSS see Churg–Strauss syndrome CVIDs see common variable immunodeficiency disorders cyclophosphamide, immunosuppression 127 cyclosporin immunosuppression 127, 127–9 lymphomas 128–9 cytokine receptors 14 cytokine therapy, immune potentiation 132–4 cytokines 11–14 actions 12–13 features 11 mycobacterial infection 45 cytomegalovirus (CMV) clinical aspects 37 renal transplantation 149 cytopenias, mechanisms of destruction 276 De Quervain’s thyroiditis 268 delayed hypersensitivity, T-cell helper cells 23–4 demyelinating diseases, CNS 289–91 dendritic cells antigen processing 22–3 defects 65–6 markers dermatitis herpetiformis (DH) 208, 250–1 DHR see dihydrorhodamine reduction diabetes mellitus 269–72 autoantibodies 272 classification 269–70 complications 271–2 environmental factors 271 1405127619_6_index.indd 350 features 270 genetic factors 271 immunological tests 272 immunopathogenesis 270, 270–1 pancreatic transplantation 271 types 270 dihydrorhodamine (DHR) reduction 321 diversity of T-cell antigen receptors DNA analysis 322–3 DNA integration, malignancy 111 DNA, recombinant DNA technology 321–4 drug-induced AIHA 279 drug-induced liver diseases 262–3 drug-induced reaction, anaphylactoid reactions 82 drug-induced thrombocytopenia 282 drugs autoimmunity 106–7, 107 immunosuppression 125–9, 126 dual recognition of peptide and MHC molecule see MHC restriction EAA see extrinsic allergic alveolitis EBA see epidermolysis bullosa acquisita EBV see Epstein–Barr virus eczema, atopic 92–4, 205 effector molecules 10–14 adaptive immunity 10 cellular immune responses 10 humoral immune responses 10 innate immunity 10 effector phase, immune responses ELISA see enzyme-linked immunosorbent assay ENA see extractable nuclear antigens encephalitis 288–9 endocarditis 237–8 endocrinology 264–74 see also hormones adrenal disease 272–3 autoimmune polyendocrine disease 274 diabetes mellitus 269–72 endocrine immunity mechanisms 264–5 gonadal disease 273 infertility 273–4 parathyroid disease 273 pituitary disease 274 thyroid disease 265–9 endogenous antigens 7, endothelial cells 15, 16 endothelium, immunological importance 15, 16 enteropathic arthritis 187 environmental factors, autoimmunity 106–7 enzyme-linked immunosorbent assay (ELISA) 315, 315–16, 316 eosinophilia 51 epidermolysis bullosa acquisita (EBA) 208 epilepsy, autoimmune disease 97 epinephrine, anaphylaxis 80, 81, 82 epitopes cryptic 103 Epstein–Barr virus (EBV) infection 36–7 lymphomas 129 evasion of immune defences bacterial infection 43, 43 helminth infections 51 mycobacterial infection 46, 46 protozoal infection 49, 49–50 evolutionary pressure exogenous antigens 7, exophthalmos, Graves’ disease 267 extensive polymorphism in MHC molecules extracorporeal photochemotherapy (photopheresis), immunosuppression 132 extractable nuclear antigens (ENA), CIE 316, 317 extrinsic allergic alveolitis (EAA) 232–4 precipitating antibodies detection 318, 318 eye diseases 217–23 see also conjunctivitis signs 219 symptoms 219 systemic diseases 218 Felty’s syndrome, neutropenia 283 fetal immune response 299–300, 300 FK506 (tacrolimus) immunosuppression 128 renal transplantation 146 focal glomerulosclerosis 171–2 food allergy and intolerance 88–91, 89, 89, 247 diagnosis 90–1 nut allergy 88, 90 oral allergy syndrome 88 food-induced gastrointestinal diseases 247–51 Freund’s complete adjuvant 138 fungal infection 47, 47–8 autoimmune disease 97 bystander damage 48 hypersensitivity 48 immunity mechanisms 47 G-CSF see granulocyte colony-stimulating factor GALT see gut-associated lymphoid tissue gastritis 244–7 atrophic 244–7 01/03/2006 15:26:20 INDEX autoantibodies 247 types 246 gastrointestinal diseases 241–53 autoimmune enteropathy 251 Crohn’s disease 251, 251–3 food-induced 247–51 GALT 241–2, 242 immunological involvement 244 infection and the gut 244 inflammatory bowel disease 251–3 intestinal immune response 243–4 normal immune mechanisms 241–3 ulcerative colitis 251, 251–3 gastrointestinal manifestations, HIV 244 GCA see giant cell arteritis gene defects, autoimmune disease 99 gene mapping 322, 322, 323 gene mutations, malignant transformation 110–12 gene therapy immune potentiation 134–5, 135 SCID 64–5, 135 genetic factors autoimmune disease 104–6, 105 Crohn’s disease 252 genetic susceptibility allergy 79–80, 80 bacterial infection 43 genomics, recombinant DNA technology 323–4 giant cell arteritis (GCA) 198, 198–9 glandular fever see infectious mononucleosis globe, eye 217, 217–18 glomerular structure 157, 157–8 glomerulonephritis acute 161–3 acute immune-complex nephritis 161, 161 acute postinfectious 162–3 acute poststreptococcal 44 anti-glomerular basement membrane disease 167–9 antineutrophil cytoplasmic antibodyassociated glomerulonephritis 169 antineutrophil cytoplasmic antibodyassociated necrotizing crescentic glomerulonephritis 170 chronic 163–7 chronic immune-complex glomerulonephritis 163–5, 164, 165 classifications 157–9 descriptive terms 158 focal 171–2 immune mechanisms 158–9 immunological mechanisms 159 lupus nephritis 167 1405127619_6_index.indd 351 membranoproliferative glomerulonephritis 165–7, 166, 166 membranous 172–3 mesangiocapillary glomerulonephritis 165–7, 166, 166 nephritic features 157 nephrotic features 157 poststreptococcal 162, 162–3, 163 rapidly progressive 167–9, 168 recurrent 177 T-cell mediated mechanisms 157 gonadal disease 273 gonococcal infection, arthritis 180 graft-versus host disease (GVHD), transplantation 153–5 granulocyte colony-stimulating factor (GCSF), immune potentiation 133–4 granulomatous diseases 227–30 classification 227 T-cell-dependent activation of macrophages 227–8 granzymes 14 Graves’ disease exophthalmos 267 immunological mechanisms 267 lymphocyte-depleting monoclonal antibody treatment 102 pretibial myxoedema 267 thyrotoxicosis 265–7 transient neonatal 305 Guillain–Barré syndrome 104, 294 gut-associated lymphoid tissue (GALT) 241–3, 242 GVHD see graft-versus host disease HAART, AIDS 71, 76 HAE see hereditary angioedema haematological diseases 275–86 see also anaemias Coombs’ tests 276, 276–7 mechanisms of destruction 275–6 haematopoietic progenitor cells 283 haematopoietic stem cell transplantation (HSCT) 152–5 haematuria asymptomatic 159–61 Henoch–Schönlein nephritis 160–1, 161 IgA nephropathy 159–60, 160 recurrent 156–7 haemophilus influenzae type B meningitis 288 hairy cell leukaemia 117 haptens Hashimoto’s thyroiditis 268 hay fever 83–5 heart disease see cardiac disease heart transplantation 151 351 heavy chains, immunoglobulin structure 7, 7–8 helminth infections 50–1 antigenic disguise 51 bystander damage 51 evasion of immune defences 51 ‘hygiene hypothesis’ 51 immunity, normal 50–1 immunosuppression of T- and B-cell responses 51 Henoch–Schönlein nephritis 160–1, 161 hepatitis see also liver diseases autoimmune 258–63 CAH 258–60 hepatitis A 253, 253–4 hepatitis B 253, 254–7, 256 hepatitis C 253, 257, 257–8 hepatitis C, blood transfusion 285–6 hepatitis D,G,E viruses 253, 258 viral 253–8 hereditary angioedema (HAE) 209 hereditary periodic fevers 200, 200 herpes virus infections 36–8 see also Epstein–Barr virus (EBV) infection clinical aspects 37 Herpes zoster, recurrent 39 histocompatibility genetics, transplantation 143–4 histocompatibility testing 324, 324–5 HIV 71 see also AIDS breast-feeding 302 chronology, HIV-induced disease 73 clinical spectrum 73, 73–4 diagnosis 75 gastrointestinal manifestations 244 immunological investigations 71, 72 neurological complications 288 skin diseases 202, 203 transmission 72–3 vaccines 141 HLA alleles, autoimmune disease 105, 105 HLA haplotypes, inheritance 144 HLA matching, renal transplantation 149 Hodgkin’s disease 117, 118 hormones see also endocrinology antibodies 305 autoimmunity 106 immune potentiation 132 Howell–Jowell bodies, coeliac disease 248, 248 HSCT see haematopoietic stem cell transplantation humoral immune responses effector molecules 10 01/03/2006 15:26:20 352 INDEX ‘hygiene hypothesis’, helminth infections 51 hyper-IgE: recurrent infection syndrome 68 hyper-IgM syndromes 57 hypersensitivity fungal infection 48 techniques, clinical immunology 317–18 tests 317–18 hypersensitivity, immediate, allergy 78–9 hypersensitivity mechanisms, autoimmune disease 107–8, 108 hypersensitivity reactions immune system 27–9, 28, 29 parasitic infection 51 hypocalcaemia, autoimmune disease 97 hypogammaglobulinaemia of prematurity, pregnancy 301 hyposensitization (specific allergen immunotherapy) 81 hypothyroidism 268–9 idiopathic Addison’s disease 272–3 idiopathic interstitial pneumonias (IIPs) 234–6 idiopathic pulmonary fibrosis (IPF) 234, 235–6 idiopathic thyroid atrophy (myxoedema) 268–9 idiotypic determinant IF see intrinsic factor antibodies IgA deficiency 58–60 nephropathy 159–60, 160 secretory 8, 242 significance 10–11 IgD, significance 10–11 IgE, significance 10–11 IgG placental transfer 300–1 significance 10–11 IgM pentamer (MW 800 kDA), schematic representation IgM, significance 10–11 IHD see ischaemic heart disease IIPs see idiopathic interstitial pneumonias IL-12 receptor deficiency 69 immediate hypersensitivity, allergy 78–9 immune complex disorders, techniques, clinical immunology 310–12 immune complexes rheumatoid arthritis 182 techniques, clinical immunology 312 Immune dysregulation, Polyendocrinopathy and X-linked Inheritance (IPEX) 274 immune manipulation 125–42 cancer immunotherapy 141–2 1405127619_6_index.indd 352 immune potentiation 132–5 immunization against infection 137–41 immunosuppression 125–32 IVIG 135–6 monoclonal antibodies 136–7 novel approaches to autoimmune disease 142 psychological factors 137 immune-mediated arthritis 180 immune-mediated neuropathies 293, 293–5, 294 immune potentiation 132–5 immune reactions, bacterial antigens 44 immune responses bacterial infection 43–4 bystander damage 40–1, 43–4, 48 factors influencing 3, 26 microorganisms 35 mycobacterial infection 45, 45–7 overview 35 parts 1–2 phases physiological outcomes 26–7 protozoal infection 48–50 viral infection 37–8, 38, 40–1 viral strategies to avoid 39–40, 40 immune system bone marrow 31 hypersensitivity reactions 27–9, 28, 29 lymphatic network 31, 31 organization overview 29–32 thymus 30–1 tissue damage 27–9 immune thrombocytopenia (ITP) 279–82 acute/chronic 281 causes 280 immunization 137–41 see also vaccines contraindications 140 infection 137–41 oral tolerance 142 passive 140 routine 139, 139–40 splenectomy 139–40 theoretical basis 137–8 travellers 140 whooping cough 139 immunodeficiency 52–77 age influence 53 combined primary T- and B-cell immunodeficiencies 61–5 CVIDs 57–60 infection 52–3, 53 primary 52 primary antibody deficiencies 53–61 primary defects in non-specific immunity 65–70 SCID 61–5, 63 secondary 52, 70–7 immunofluorescence 207, 320 ALL 319 immunofluorescence, indirect 312–15, 313, 314 immunoglobulin genes 8–9, immunoglobulin, intravenous, Kawasaki’s disease 135 immunoglobulin replacement therapy 61 immunoglobulins classes functions isotypes 10–11 measurement 308, 308 protein electrophoresis 308–10 qualitative investigation 308–10 structure 7, 7–8 immunomodulation by IVIG 135–6 immunosuppression 125–32 drugs 125–9, 126 immunosuppression of T- and B-cell responses, helminth infections 51 immunosurveillance, cancer 142 immunotherapy, cancer 141–2 impaired cell-mediated immunity 36 indirect immunofluorescence 312–15, 313, 314 infection 33–51 autoimmunity 106 bacterial 41–4 conjunctival 219 factors influencing 33 fungal 47–8 and the gut 244 helminth 50–1 immunization 137–41 immunodeficiency 52–3, 53 immunosuppressed host 76–7, 77 macrophages 34–5, 35, 48–9, 50 mechanical barriers 34, 34 mycobacterial 45–7 neuroimmunology 287–9 non-specific resistance 34–5 opportunistic 76–7, 77 parasitic 48–51 pregnancy 299–302 protozoal 48–50 renal transplantation 150 resistance, normal 34–6 skin diseases 202 specific resistance 35–6 viral 36–41 infectious mononucleosis (‘glandular fever’) 36 infertility 273–4 inflammation 16, 18, 27 01/03/2006 15:26:20 INDEX allergy 86, 87 infection 34, 34 inflammatory arthritis or synovitis, patterns of joint disease 178–9, 179 inflammatory bowel disease 251–3 inflammatory muscle disease 199–200 inheritance coeliac disease 249 HLA haplotypes 144 innate immunity 1–2, 2, 66 effector molecules 10 innate responses, functional basis 15–21 integrins 14–15, 15 interferons, immune potentiation 132–3, 133 interleukin-1, actions 11 interleukins, actions 12–13 internet sites, clinical immunology and allergy 327–8 interstitial lung disease 230–6, 235 causes 231 intestinal immune response 243–4 intravenous immunoglobulin (IVIG) 135–6, 136 Kawasaki’s disease 135 intrinsic factor (IF) antibodies 246–7, 247 IPEX see Immune dysregulation, Polyendocrinopathy and X-linked Inheritance IPF see idiopathic pulmonary fibrosis IRAK-4 deficiency 65 ischaemic heart disease (IHD), rheumatoid arthritis 184–5 isotope switching, B cells 25 ITP see immune thrombocytopenia IVIG see intravenous immunoglobulin JIA see juvenile idiopathic arthritis joints and muscles 178–200 arthritis and infection 179–80 autoinflammatory syndromes 200, 200 chronic arthritis, children 188–9 GCA 198–9 hereditary periodic fevers 200, 200 inflammatory muscle disease 199–200 joint, diagrammatic representation 179 mixed connective tissue disease 195 myositis 199–200 PAN 197–8 patterns of joint disease 178–9 PMR 198–9 rheumatoid arthritis 180–5 scleroderma 197 seronegative spondyloarthritis 185–8 Sjögren’s syndrome 196–7 SLE 189–95 systemic vasculitis 197–9 juvenile idiopathic arthritis (JIA) 188, 188–9 1405127619_6_index.indd 353 Kaposi’s sarcoma 71 renal transplantation 150 Kawasaki’s disease 239 intravenous immunoglobulin 135 keratitis 220–1 key molecules 2–15 accessory molecules 9–10 adhesion molecules 14–15, 15 effector molecules 10–14 molecules recognized by immune systems 3–4 receptors for effector functions 14 recognition molecules 4–9 kidney diseases 156–77 see also glomerulonephritis chronic renal failure 176–7, 177 clinical syndromes 156–7 glomerulonephritis, acute 161–3 glomerulonephritis, chronic 163–7 glomerulonephritis, classifications 157–9 glomerulonephritis, rapidly progressive 167–9 glomerulonephritis, recurrent 177 haematuria, asymptomatic 159–61 nephrotic syndrome 169–75 tubulointerstitial nephropathy (TIN) 175–6 kidney transplantation see renal transplantation Lambert–Eaton myasthenia (LEMS) 287 late-phase response (LPR), allergy 79 latent state, viral infection 39–40 latex rubber, anaphylaxis 81, 82 LE see lupus erythematosus LEMS see Lambert–Eaton myasthenia leprosy 46, 46–7 leucocyte adhesion deficiency 68 leucocyte differentiation pathway, leukaemia 113 leucocyte–endothelial interactions, adhesion molecules 15 leukaemia 112–17 acute 112–15, 113 ALL 319 AML 153, 324 ATL 117 BMT 153 chronic 113, 115–17 complications 114, 115 diagnosis 114 hairy cell 117 leucocyte differentiation pathway 113 markers 114 onset age 113 origins 116 Sézary syndrome 116 353 techniques, clinical immunology 319 treatment objectives 113 light chains, immunoglobulin structure 7, 7–8 limbal vernal conjunctivitis 83 Listeria monocytogenes meningitis, immunosuppression, SLE 76 listeria, pregnancy 299 liver diseases 253–63 see also hepatitis alcohol-induced 262–3 autoimmune 258–63 CAH 258–60 drug-induced 262–3 PBC 260–2 viral hepatitis 253–8 liver transplantation 150–1, 262 LPR see late-phase response lung diseases 227–37 lung transplantation 151 lupus erythematosus (LE) 212, 213 see also systemic lupus erythematosus (SLE) features 213 lupus nephritis 167 Lyme disease, arthritis 180 lymph nodes distribution, lymphomas 119 lymphadenopathy, persistent generalized 72 lymphatic network, immune system 31, 31 lymphocyte-depleting monoclonal antibody treatment Graves’ disease 102 MS 102 lymphocyte transformation 175, 202, 320 lymphocytes adaptive immune responses 21 assessment 318–20 development functional tests 320 GALT 241–3 quantification 318–20 recirculation 31, 31 role 1–2 techniques, clinical immunology 318–20 lymphomas 117–20 ATL 117 B-cell 119 Burkitt’s lymphoma 37 cyclosporin 128–9 EBV induced 128–9 Hodgkin’s disease 117, 118 immunopathogenesis 119 lymph nodes distribution 119 multiple myeloma 120, 120–2 non-Hodgkin’s lymphoma 118–20 renal transplantation 150 01/03/2006 15:26:21 354 INDEX lymphoproliferative disorders 110–24 see also malignancy immunodeficiency 70 leukaemia 112–17 lymphomas 117–20 malignant transformation 110–12, 111 plasma cell dyscrasias 120–4 techniques 111 lytic lesions, multiple myeloma 121 MCN see minimal-change nephropathy MCQs 329–46 macrophages 16–17, 18 activation 48–9 corticosteroids 125–6 defects of effector functions 68–9 infection 34–5, 35, 48–9, 50 protozoal infection 50 major histocompatibility complex molecules (MHC) 5–6, transplantation 143, 144 malaria, cerebral 48 malignancy see also lymphoproliferative disorders Burkitt’s lymphoma 37 DNA integration 111 Kaposi’s sarcoma 71 malignant transformation 110–12, 111 viral infection 37, 38–9, 39 mannan-binding lectin (MBL), complement system 19 mast cell triggering, allergy 79 MBL see mannan-binding lectin MDP see muramyl dipeptide ME see myalgic encephalomyelitis membranous glomerulonephritis 172–3 meningitis, haemophilus influenzae type B meningitis 288 meningococcal infection, arthritis 180 MGUS see monoclonal gammopathy of unknown significance MHC see major histocompatibility complex molecules MHC class I antigens 6, MHC class II antigens 6–7, MHC class III region 6, MHC restriction 6, 6–7 microarrays, recombinant DNA technology 323–4 microbial antigens, detection 312, 313 microorganisms, immune responses 35 minimal-change nephropathy (MCN) 170–1 T-cell mediated reactions 171 minocycline-induced SLE 107 mixed connective tissue disease 195 MMF see mycophenolate mofetil 1405127619_6_index.indd 354 molecular mimicry, autoimmunity 104, 104 molecules, key see key molecules molecules recognized by immune systems 3–4 monoclonal antibodies 307, 307 immune manipulation 136–7 immunosuppression 129, 129 tumour antigens 141–2 uses 136–7 monoclonal gammopathies 295 monoclonal gammopathy of unknown significance (MGUS) 122–3, 124 monocytes assessment 320–1 defects 65–6 MS see multiple sclerosis multifocal motor neuropathy 295 multiple myeloma 120, 120–2, 124 bone marrow studies 122 diagnosis 120 lytic lesions 121 TIN 175–6 multiple sclerosis (MS) 289–91 apoptosis of oligodendrocytes 291 CSF investigations 289, 289–90 environmental factors 290–1 genetic factors 291 immunopathogenesis 289 infective organism 291 lymphocyte-depleting monoclonal antibody treatment 102 muramyl dipeptide (MDP), adjuvants 138–9 mutations, parasitic infection 48 myalgic encephalomyelitis (ME) 40, 41 myasthenia gravis 97, 291–3, 292, 293 heterogeneity 293 neonatal 97 mycobacterial infection 45–7 cytokines 45 damage by immune responses 46–7 evasion of immune defences 46, 46 immune responses 45, 45–7 T cells 45 tuberculosis 45 mycophenolate mofetil (MMF) immunosuppression 127 renal transplantation 146 myeloma kidney, TIN 175–6 myocardial infarction, renal transplantation 150 myocarditis 237–8 myositis 199–200 myxoedema (idiopathic thyroid atrophy) 268–9 NBT test see nitroblue tetrazolium test neonatal alloimmune diseases 282 neonatal myasthenia gravis 97 neonatal thrombocytopenia 282 nephrotic syndrome 157, 169–75 amyloid disease 173, 173–4 features 169–70 focal glomerulosclerosis 171–2 MCN 170–1 membranous glomerulonephritis 172–3 neuroimmunology 287–96 demyelinating diseases, CNS 289–91 immune-mediated neuropathies 293–5 infection 287–9 MS 289–91 myasthenia gravis 291–3, 292, 293 neuromuscular junction, autoimmune diseases 291–3, 292 neuromuscular junction, autoimmune diseases 291–3, 292 neutropenia 66–8, 67, 282–3 causes 282 Felty’s syndrome 283 neutrophil function, immunodeficiency 66–8, 68 neutrophil polymorphonuclear leucocytes 16 neutrophils, assessment 320–1, 321 nickel dermatitis 204 nitroblue tetrazolium (NBT) test 321 NK cells development recognition molecules role 20–1, 21 non-Hodgkin’s lymphoma 118–20 non-specific interstitial pneumonia (NSIP) 236 Northern blotting technique 322 novel approaches, autoimmune disease 142 NSIP see non-specific interstitial pneumonia nut allergy 88, 90 oophoritis 273 opportunistic infection 76–7, 77 opsonins 20 infection 34 opsonization 17–18, 18 optic neuritis 290 oral tolerance, autoimmune disease 142 organ-specific autoimmune disease 96 organ-specific diseases, pregnancy 304 PA see pernicious anaemia PAMPs see pathogen associated molecular patterns PAN see polyarteritis nodosa pancreatic transplantation 151 diabetes mellitus 271 01/03/2006 15:26:21 INDEX parainfectious encephalitis 288 paraneoplastic syndromes 295, 295 parasite-specific IgE antibodies 50–1 parasitic infection 48–51 bystander damage 51 helminth infections 50–1 hypersensitivity reactions 51 mutations 48 protozoal infection 48–50 parathyroid disease 273 paroxysmal nocturnal haemoglobinuria (PNH) 279 pathogen associated molecular patterns (PAMPs) pattern recognition receptors (PRRs) 3, 4, 4, 65–6 PBC see primary biliary cirrhosis PCR see polymerase chain reaction pemphigoid gestationis 208 pemphigus 206 pemphigus vulgaris 207–8 perennial allergic rhinitis 84 perforin 14 pericarditis 237 peripheral neuropathy 293–5 peripheral tolerance, autoimmunity 100–2, 101, 102–3 pernicious anaemia (PA) 244–7 features 246 persistent generalized lymphadenopathy 72 phagocytic cells 16 functions 17 infection 34 phagocytic receptors and complement, infection 34–5 phagocytosis, techniques, clinical immunology 321 photopheresis, immunosuppression 132 physical agents, autoimmunity 107 pituitary disease 274 placenta pregnancy 297–9 relationships 298 placental transfer autoimmunity 96 IgG 300–1 plasma cell dyscrasias 120–4 α-chain disease 124 benign paraproteinaemia 122–3 MGUS 122–3, 124 multiple myeloma 120, 120–2, 122 Waldenström’s macroglobulinaemia 120, 122, 123–4 plasma exchange, immunosuppression 131 plasmapheresis, immunosuppression 131, 132 1405127619_6_index.indd 355 PMR see polymyalgia rheumatica pneumococcal sepsis, splenectomy 140 pneumocystis pneumonia, immunosuppression 128 pneumonias 225–7 chronic lymphatic leukaemia 226 IIPs 234–6 NSIP 236 pneumocystis pneumonia 128 PNH see paroxysmal nocturnal haemoglobinuria polyarteritis nodosa (PAN) 197–8, 198 polyclonal antibodies 307 polymerase chain reaction (PCR) 322–3, 323 polymorphonuclear leucocytes, infection 34 polymyalgia rheumatica (PMR) 198–9 polypeptide vaccines 141 postviral fatigue syndrome 40, 41 pre-eclampsia, pregnancy 303–4 precipitating antibodies 318, 318 pregnancy 297–305 abortions, recurrent 302 alloimmunization 304 antibodies 305 breast-feeding 301–2 contraceptive vaccines 305 disorders 302–5 fetal immune response 299–300, 300 Graves’ disease, transient neonatal 305 hypogammaglobulinaemia of prematurity 301 immunological mechanisms 297–9 infection protection 299–302 listeria 299 maternal infection 299 organ-specific diseases 304 placenta 297–9 placental transfer of IgG 300–1 pre-eclampsia 303–4 rheumatic diseases 303 SLE 302–3 transient neonatal Graves’ disease 305 uterus 297 pretibial myxoedema, Graves’ disease 267 primary amenorrhoea 273 primary antibody deficiencies 53–61 primary antiphospholipid antibody (APA) syndrome 283 clinical presentations 284 cf SLE 283 primary biliary cirrhosis (PBC) 260–2 features 261 tests 307 progressive multifocal leucoencephalopathy 289 protein electrophoresis 308, 308–10 355 protein loss, immunodeficiency 70 protein–polysaccharide conjugate vaccines 138, 138 proteinuria, persistent 157 protozoal infection 48–50 bystander damage 51 evasion of immune defences 49, 49–50 immune responses 48–50 macrophages 50 PRRs see pattern recognition receptors psoriasis 205–6 immunological mechanisms 206 T-cell mediated 205 psoriatic arthritis 187 psychological factors, immune manipulation 137 pulmonary eosinophilia 231–3 causes 232 classification 232 pulmonary fibrosis 231 IPF 234, 235–6 rheumatoid arthritis 184 pulmonary vasculitis 236–7 pyogenic arthritis 179 quality assurance 307 radioallergosorbent technique (RAST) 317, 317–18 radioimmunoassay 315, 315, 315–16 rapamycin, immunosuppression 128 rapidly progressive glomerulonephritis (RPGN) 167–9, 168 RAST see radioallergosorbent technique Raynaud’s phenomenon 214 receptors for effector functions 14 receptors, phagocytic cells 17 recognition molecules 4–9 NK cells recognition phase, immune responses recombinant DNA technology 321–4 diagnostic implications 323 DNA analysis 322–3 genomics 323–4 microarrays 323–4 recombinant vaccines 141 recombination, immunoglobulin genes 8, Reiter’s syndrome conjunctivitis 220 reactive arthritis 186–7 relapsing polychondritis 187 renal failure, chronic 176–7, 177 see also kidney diseases renal transplantation 144–50 acute rejection 146, 147, 147 allograft response 147–8, 148 complications 148–50 01/03/2006 15:26:21 356 INDEX renal transplantation (continued) cytomegalovirus infection 149 cytotoxic antibodies 145 disease recurrence 177 donors 144–5 graft survival 148 HLA matching 149 infection 150 Kaposi’s sarcoma 150 lymphomas 150 myocardial infarction 150 post-transplantation period 145–6 recipients 144–5 rejection 145–8 replacement therapy, immunoglobulin 61 respiratory allergy 83–8 respiratory burst, techniques, clinical immunology 321 respiratory infections 225–7 bacterial pneumonia 226 causes 226 chronic lymphatic leukaemia 226 classification 225 patterns 227 pneumonia 225–7 sarcoidosis 220, 229–30 tuberculosis 45, 45, 228, 228–9 restriction fragment length polymorphisms (RFLP) 322 retroviruses 74 RFLP see restriction fragment length polymorphisms rheumatic diseases, pregnancy 303 rheumatic fever bacterial infection 43–4 endocarditis 238 rheumatic heart disease 43–4 rheumatoid arthritis 180–5 aetiology 183–4, 184 anti-tumour necrosis factor antibodies 131 autoimmune response 183 autoimmunity 95 B cells 182–3, 183 CD4+ T cells 182 diagnosis 180 features 181 IHD risk 184–5 immune complexes 182 immunopathogenesis 182–3 management 185 outcome 184–5 pathology 181–2 prognosis 185 pulmonary fibrosis 184 serology 180–1 T cells 182–3, 183 1405127619_6_index.indd 356 TNF-α 182 rhinitis 83–5 causes 84 RPGN see rapidly progressive glomerulonephritis rubella 139 sarcoidosis 229–30 conjunctivitis 220 systemic involvement 230 schistosomiasis 50 SCID see severe combined immunodeficiencies scleritis 221 scleroderma 197 classification 214 sclerosis, systemic 213–16 seasonal allergic rhinitis 83–5 seasonal conjunctivitis 83 secondary immunodeficiency 52, 70–7 causes 70–2 secretory IgA 242, 242 schematic representation selectins 14–15, 15 self-antigens 3–4 autoimmune disease 98 self-sustaining autoreactive pathogenic process, autoimmunity 103, 103–4 self-tolerance, autoimmunity 98–9 septic arthritis 179, 179–80 sequestration, bacterial infection 43 seronegative spondyloarthritis 185–8 serum protein electrophoresis 308, 308–10 severe combined immunodeficiencies (SCID) 61–5 BMT 154–5 clues 63 examples 63 features 64 gene therapy 64–5, 135 lymphocytes 64 Sézary syndrome 116 shingles 117, 118 Sjögren’s syndrome 196, 196–7, 262 skin diseases 201–16 allergy 91–4 alopecia areata 209 angioedema 91–2, 209 atopic eczema 92–4, 205 autoimmune 206–9 bullous 206–8 bullous pemphigoid 208 C1 inhibitor deficiency 209–10, 210 cold sores 202, 203 contact dermatitis 94, 203–5, 205 cryoglobulinaemia 211–13 DH 208 EBA 208 HIV 202, 203 immunofluorescence 207 infection 202 LE 212, 213, 213 nickel dermatitis 204 pemphigoid gestationis 208 pemphigus 206 pemphigus vulgaris 207–8 proinflammatory factors 201 psoriasis 205–6 Raynaud’s phenomenon 214 scleroderma 197, 214 systemic diseases 209–16 systemic sclerosis 213–16 T-cell-mediated 202–6 ultraviolet light 201 urticaria 91–2 vasculitis 210–11 vitiligo 208 skin grafting 151–2 SLE see systemic lupus erythematosus somatic hypermutation 11 Southern blotting technique, gene mapping 322, 322, 323 specific allergen immunotherapy (hyposensitization), allergy 81 sperm, antibodies 305 spleen 31, 32 splenectomy 71 AIHA 277, 278 immunization 139–40 pneumococcal sepsis 140 SSPE see subacute sclerosing panencephalitis stem cell transplantation 152–5 Stevens–Johnson syndrome 219–20 streptococcal infection, β-haemolytic, complications 43 streptococcal toxic shock syndrome 42 subacute sclerosing panencephalitis (SSPE) 289 superantigens bacteria as 42, 42 diseases, associated 42 synthesised peptides vaccines 141 systemic diseases, skin diseases 209–16 systemic lupus erythematosus (SLE) 189–95 aetiology 193, 193 cf APA syndrome 283 apoptosis 194 autoantibody production 193–4 cerebral 295–6, 296 complement deficiency 193, 194 damaged cell clearance 194 diagnosis 190 01/03/2006 15:26:21 INDEX differential diagnosis 191, 192 drug-induced 191 drugs 194 features 189, 189–90 hormones 195 laboratory findings 190–1, 191 Listeria monocytogenes meningitis 76 management 191–2 minocycline-induced 107 nuclear antigens 191 organ involvement 189 pathogenesis 193 pregnancy 302–3 prognosis 192–3 serological changes 192 tests 307 ultraviolet light 194–5 systemic sclerosis 213–16 autoantibodies 216 pathogenesis 215 systemic vasculitis 197–9 T-cell activation, bacterial infection 42 T-cell dependence, bacterial infection 41 T-cell-dependent activation of macrophages, granulomatous diseases 227–8, 228 T-cell help 23–5 T-cell helper cells 23–4 delayed hypersensitivity 23–4 T-cell mediated mechanisms, glomerulonephritis 157 T-cell mediated psoriasis 205 T-cell mediated reactions, MCN 171 T cell-mediated responses, adaptive immune responses 23–5 T-cell-mediated skin diseases 202–6 T-cell receptors (TCRs) structure T-cell selection, thymus 100 T-cell vaccines, autoimmune disease 142 T cells atopic eczema 94 autoimmunity 100, 100–1, 101 mycobacterial infection 45 rheumatoid arthritis 182–3, 183 selection 30 T-independent antigens, B cells 25–6 T-lymphocyte activation pathways, tests 320 Takayasu’s disease 239–40 TCRs see T-cell receptors techniques, clinical immunology 306–25 see also tests allergy 317–18 ANAs 314–15 antibodies to microbial antigens 312, 313 1405127619_6_index.indd 357 autoantibodies 312–17 biopsy material 316 C3 nephritic factor (C3 NeF) 312 chemotaxis 321 CIE 316, 316 complement breakdown products 311–12 complement components 310–12, 311, 311 CSF 310, 310 DNA analysis 322–3 ELISA 315, 315–16, 316 functional assays 312 gene mapping 322, 322 genomics 323–4 histocompatibility testing 324, 324–5 hypersensitivity 317–18 immune complex disorders 310–12 immune complexes 312 immunoglobulins 308–10 immunoglobulins measurement 308, 308 indirect immunofluorescence 312–15, 313, 314 leukaemia 319 lymphocytes 318–20 microarrays 323–4 monocytes 320–1 neutrophils 320–1 Northern blotting technique 322 PCR 322–3, 323 phagocytosis 321 precipitating antibodies 318, 318 protein electrophoresis 308, 308–10 quality assurance 307 radioimmunoassay 315, 315, 315–16 RAST 317, 317–18 recombinant DNA technology 321–4 respiratory burst 321 RFLP 322 serum protein electrophoresis 308, 308–10 Southern blotting technique 322, 322, 323 total serum IgE 318 urine 310 tests see also techniques, clinical immunology allergy 317–18 AMA 307 antibodies 54 Coombs’ tests 276, 276–7 diabetes mellitus 272 hypersensitivity 317–18 neutrophils 320–1, 321 PBC 307 reasons 306 SLE 307 T-lymphocyte activation pathways 320 TGF-β see transforming growth factor-β 357 thiopurines, immunosuppression 126–7, 127 thrombocytopenia drug-induced 282 immune 279–82 neonatal 282 thymic tolerance, autoimmunity 99–100 thymus immune system 30–1 T-cell selection 100 thymus-dependent antigens thymus-independent antigens thyroid disease 265, 265–9, 266 autoimmune 269, 269 De Quervain’s thyroiditis 268 Graves’ disease 265–7 Hashimoto’s thyroiditis 268 hypothyroidism 268–9 idiopathic thyroid atrophy (myxoedema) 268–9 thyrotoxicosis 265–7 thyrotoxicosis 265–7 TIN see tubulointerstitial nephropathy tissue damage autoimmune disease 107–8 immune system 27–9 mechanisms 107–8 TLI see total lymphoid irradiation TLRs see toll-like receptors TNF-α see tumour necrosis factor-α toll-like receptors (TLRs) 4–5 defective pathways immunodeficiency 66 tonsillitis, acute bacterial 41 total lymphoid irradiation (TLI), immunosuppression 131–2 total serum IgE 318 toxic shock syndrome, streptococcal 42 transforming growth factor (TGF)-β, fibrosis transforming growth factor (TGF)–β transient hypogammaglobulinaemia of infancy 55 transient neonatal Graves' disease 305 transplantation 143–55 BMT 152, 152–5, 153 corneal grafting 152 EBV induced lymphoma 129 GVHD 153–5 heart 151 histocompatibility genetics 143–4 HSCT 152–5 liver 150–1, 262 lung 151 MHC 143, 144 pancreatic 151 renal 144–50 01/03/2006 15:26:21 358 INDEX transplantation (continued) skin grafting 151–2 stem cell 152–5 xenotransplantation 155 triggers, autoimmunity 104–7 tuberculosis 45, 228–9 risk factors 45, 228 tubulointerstitial nephropathy (TIN) 175–6 acute drug-induced 175 functional defects 175 multiple myeloma 175–6 myeloma kidney 175–6 tumour antigens, monoclonal antibodies 141–2 tumour necrosis factor (TNF)-α, rheumatoid arthritis 182 tumour suppressor genes 111–12 type I-IV reactions, immune system 27–9, 29 ulcerative colitis 251, 251–3 ultraviolet light immunosuppression 132 skin diseases 201 SLE 194–5 up-regulation, co-stimulatory molecules 106 urticaria 91–2, 92 urticarial vasculitis 92, 211 1405127619_6_index.indd 358 uveitis 221–3 classification 222 vaccines 137–41 see also immunization advantages/disadvantages 138 contraceptive 305 development 140–1 HIV 141 polypeptide 141 protein–polysaccharide conjugate vaccines 138, 138 recombinant 141 side-effects 139 synthesised peptides 141 T-cell vaccines 142 Varicella zoster virus (VZV) 117, 118 clinical aspects 37 zoster infection 39, 117, 118 vasculitis 210–11 ANCA 211 causes 210 classification 211 systemic 197–9 urticarial 92, 211 vernal conjunctivitis 83 viral arthritis 180 viral hepatitis 253–8 viral infection 36–41 bystander damage 40–1 direct effects of viruses 38–9 Epstein–Barr virus infection 36–7 herpes virus infections 36–8, 37 immune responses 37–8, 38 infectious mononucleosis (‘glandular fever’) 36 latent state 39–40 malignancy 37, 38–9, 39 speculative effects 41 vitiligo 208 vulvo-vaginitis, acute 47 VZV see Varicella zoster virus Waldenström’s macroglobulinaemia 120, 122, 123–4 wasp venom, anaphylaxis 80 Wegener’s granulomatosis 236, 236–7 whooping cough, immunization 139 World Wide Web, clinical immunology and allergy 327–8 X-linked agammaglobulinaemia (Bruton’s disease) 55–7 xenotransplantation 155 zoster infection 39, 117, 118 01/03/2006 15:26:22 ... of febrile episode > days 3–7 days 1405 127 619_4_010.indd 20 0 1–3 days Cryopyrin 1 2 days 01/03 /20 06 16: 52: 06 CHAPTER 11 11 Skin Diseases 11.1 Introduction, 20 1 11 .2 Infections and the skin, 20 2... skin, 20 2 11.3 T-cell-mediated skin disease, 20 2 11.3.1 Contact dermatitis, 20 3 11.3 .2 Atopic eczema, 20 5 11.3.3 Psoriasis, 20 5 11.4 Autoimmune skin disease, 20 6 11.4.1 Bullous skin disease, 20 6... of 28 g/l (NR 7 .2 19.0), with a slightly raised IgM of 2. 8 g/l (NR 0.5 2. 0) and a normal IgA Schirmer’s test was performed (see section 10.8 .2) The test was markedly abnormal as only 3.5 mm of