1、Case presentation: Rheumatoid Arthritis,44 year old woman with the new onset of progressive arthritis over the past 3 months, now unable to work - swelling, pain, and stiffness in fingers, hands, wrists, elbows, shoulders, knees, ankles, and feet - morning stiffness 8 hours, fatigueExam reveals diff
2、use symmetrical synovitis and subcutaneous nodulesX-rays of the hands show early marginal erosions,(Autoimmunity & Autoimmune Disease),Section 1 Overview Section 2 mechanism of autoimmune disease Section 3 Causes of Damage in Autoimmune Diseases Section 4 Examples of autoimmune diseases Section 5 Tr
3、eatment of autoimmune diseases,Section 1 Overview,autoimmunity Specific adaptive immune responses mounted against self antigens autoimmune disease(AID) tissue damage and clinical symptom is the result of autoimmunity auto-antibody & auto-reactive T cell Produce in the autoimmunity of Antibody and re
4、active T cell,can be single organ or multisystem diseases can be more than one autoantibody in a given disease loss,Causes for Loss of self-tolerance Bypass of helper T-cell tolerance modification of antigen (via drugs, microorganisms) expression of second signal from macrophages stimulated from inf
5、ections Molecular mimicry infectious agents appear similar to self-antigens (streptococcal antigen and myocardium) Polyclonal lymphocyte activation endotoxins cause such activation independent of specific antigens,Imbalance of suppressor-helper T cell function any loss of suppressor T-cell function
6、may contribute to autoimmunity Emergence of sequestered antigens following trauma or infection, previously unseen antigens may emerge (bullous pemphigoid following a burn),The immunity regulates,Organ-specific diseases Systemic diseases,Section 2 mechanism of autoimmune disease,(一)Damage produced by
7、 immune attack can produce altered forms of self antigens,Some body sites are immunologically priviledged,Damage to an immunologically privileged site can induce an autoimmune response,Several ways in which infectious agents could break self tolerance,2 Damage produced by immune attack can produce a
8、ltered forms of self antigens,molecular mimicry by cross-reactive microbial antigen can stimulate autoreactive B and T cell,Increased HLA class II antigens expression,Limitations in Tolerance Mechanisms in,Association of infection with autoimmune disease,Section 3 Causes of Damage in Autoimmune Dise
9、ases,The most damage of autoimmune disease come from Antibody-mediated damage Associated with antibodies to self-proteins cleaved by cytotoxic Mononuclear infiltrate consisting primarily of T-cells (primarily CD4+),Autoimmune diseases mediated by cytotoxic antibodies (Type II),Autoimmune diseases me
10、diated by immune complexes (Type III),Autoimmune diseases mediated by T-cells (Type IV),Autoimmunity involves T cells,Ability of a T cell to respond is determined by MHC genotype It has been hypothesized that susceptibility to an autoimmune disease is determined by differences in the ability of alle
11、lic variants of MHC molecules to present autoantigenic peptides Alternatively, self peptides may drive the positive selection of developing thymocytes that are specific for particular autoantigens.,Autoimmune diseases patient main auto-antibody of inside,anti-nucleus antibody( ANA)anti-changes IgG a
12、ntibody( type rheumatism factor, RF)anti-phospholipid antibody( APL antibody)anti-neutrophil cytoplasm antibod( ANAC),Section 4 Examples ofautoimmune diseases,Examples of autoimmune diseases,(1) rheumatoid arthritis(2) system lupus erythematosus(3) myasthenia gravis(4) Grave s disease(5) multiple sc
13、lerosis,Rheumatoid arthritis non-suppurative proliferative synovitis which leads to descruction of articular cartilage and progressive disabling arthritis extra-articular manifestations may strongly resemble SLE or scleroderma occurs in 1% of population usual onset in decades 4 and 5 3-5X more commo
14、n in women than in men,Rheumatoid arthritis Etiology and Pathogenesis initiated by activation of T-helper cells which produce cytokines and activate B cells to produce antibodies HLA-DR4/DR1 associated with increased incidence 80% of patients with rhematoid factors (antibodies against Fc portion of
15、IgG) precise trigger which initates destructive immune response is not known,Rhematoid arthritis Clinical course symmetrical, polyarticular arthritis weakness, fever, malaise may accompany joint symptoms stiffness of joints in AM early, then progresses to claw-like deformities anemia of chronic dise
16、ase present in late cases severely crippling in 15-20 years, life expectancy reduced 4-10 years amyloidosis develops in 5%-10% of patients,Rheumatoid arthritis Pathology symmetric arthritis affecting primarily small joints (proximal interphalangeal and metacarpophalangeal joints) chronic synovitis,
17、proliferation of synovial lining cells (villous projections) subsynovium filled with inflammatory cells - lymphoid nodules pannus - highly vascularized, inflamed, reduplicated synovium fibrosis and calcification follow leading to ankylosis synovial fluid contains neutrophils,Rheumatoid arthritis Pat
18、hology (continued) rheumatoid nodules - 25% of patients - subcutaneous nodules along extensor surfaces of forearms or other sites of trauma firm, non-tender, up to 2 cm. diameter dermal nodules of fibrinoid necrosis surrounded by macrophages and granulation tissue acute necrotizing vasculitis of art
19、eries in florid cases progressive interstitial fibrosis of lungs in some cases,Juvenile rheumatoid arthritis chronic idiopathic arthritis in children some variants involve few large joints (pauciarticular), do not have rheum. factor others assoc. with HLA-B27 uveitis may be present Stills disease -
20、acute febrile onset, leukocytosis, hepatosplenomegaly and lymphoadenopathy and skin rash,Classification Criteria for Rheumatoid Arthritis (ARA, 1987),Morning stiffness 1 hour Three or more joint area arthritis Hand arthritis Symmetrical involvement Nodules Serum rheumatoid factor X-ray changes,4 or
21、more criteria for 6 weeks = rheumatoid arthritis with sensitivity 77-95%, specificity 85-98% (Moens HJB, et al. J Rheumatol 1992;19:198-203),Do I (Does My Patient) Have Rheumatoid Arthritis?,Unlikely if: No joint inflammation No systemic signs/Excess systemic signs Not symmetrical Atypical joints in
22、volved,1% of the population has rheumatoid arthritis. It is the most common autoimmune arthritis, but it is far less common than osteoarthritis and other causes of joint pain,Rheumatoid Factor,IgM,IgG,Fc Receptor of IgG,The Role of RF Testing:,RF is the best (generally available) single test to asse
23、ss prognosis in RA RF has limited utility as a diagnostic test RF correlates with disease activity, but not strongly,Systemic Lupus Erythematosus (SLE) multisystem autoimmune disease affects skin, kidneys, serosal surfaces, joints, CNS and heart many autoantibodies Table 5-5 (Kumar) demonstrates dia
24、gnostic criteria incidence of up to 1:2500 people, 10X more common in women usually arises in second-third decades, more common in black Americans,SLE Etiology and Pathogenesis - failure to maintain self-tolerance,SLE Antinuclear antibodies antibodies to DNA antibodies to histones antibodies to non-
25、histone proteins bound to RNA antibodies to nucleolar antigens ANA test is sensitive, but not specific,SLE Genetic factors 30% concordance in monozygotic twins association between SLE and HLA-DQ loci,SLE Non-genetic factors drugs such as procainamide and hydralazine may causeLE like signs and sympto
26、ms androgens protect, estrogens enhance likelihood of developing LE UV light may trigger development of LE,SLE Immunologic factors B-cell hyperreactivity is a feature of LE, caused by excess T-helper activity how self-tolerance is lost is not known,SLE Mechanisms of tissue injury type III hypersensi
27、tivity reactions with DNA-anti-DNA complexes depositing in vessels LE cell - any phagocytic leukocyte (neutrophil or macrophage) that engulfs denatured nuclei of injured cells (evidence of cell injury and exposed nuclei),SLE Clinical manifestations young women, classic butterfly rash on face fever,
28、joint pain, pleuritic chest pain, photosensitivity renal failure hematologic anomalies ANAs present in 100% of patients, anti-double-stranded DNA much more specific for LE some with rapid downhill progression 10 year survival is 70%, death from CNS and renal involvement,SLE Vasculitis - acute necrot
29、izing vasculitis of small arteries or arterioles in any organs Skin lesions - erythematous maculopapular eruption over malar regions which is exacerbated by sun-exposure; liquefactive degeneration of basal layer, interface dermatitis and superficial and deep perivascular lymphocytic infiltrate depos
30、its of immunoglobulins along DEJ some patients have discoid LE with no systemic involvement,SLE Serosal involvement - pericardium and pleura develop serosanguinous exudate Nonbacterial verrucous endocarditis - Libman-Sacks endocarditis - multiple warty deposits on any valve and either surface of the
31、 leaflets Joint involvement - no striking anatomic changes nor deformities, non-specific lymphocytic infiltrates CNS involvement - multifocal cerebral infarcts from microvascular injury,SLE Renal involvement mesangial lupus nephritis - 20% of cases; mild symptoms focal proliferative glomerulonephrit
32、is - 25% of cases; mild clinical symptoms diffuse proliferative glomerulonephritis - 45%-50% of cases;very symptomatic with hematuria, proteinuria and hypertension - renal failure membranous glomerulonephritis - 15% of cases; severe proteinuria and nephrotic syndrome,Mechanism of myasthenia gravis,M
33、echanism of Grave s,Section 5 Treatment of autoimmune diseases,Prevent with control the infection of theoriginal The use of immunosuppressive maneuvre Anti- inflammatory therapy Apply the cytokine Apply the specific antibody Take orally the autoantigen to induce tolerance HSC transplantation,The use
34、 of immunosuppressive maneuvre Anti-Cytokine Therapy,The new: anti-TNF, anti-IL-1, more coming Highly effective in RA, promising in other conditions The old: NSAIDs (prostaglandin inhibitors) Weak, but beneficial in Still s disease, gout, rheumatic fever+ as adjunctive therapy The others: thalidomid
35、e (anti-IL-12), cyclosporine (anti-IL-2) Promising benefits, side effects too high with current forms,Useful web sites and reading ? 1. Immunologic Diseases http:/www.mic.ki.se/Diseases/c20.html excellent resource A comprehensive list of links to websites related to immune diseases.?2. The PathoPlus
36、 Page http:/ Good introductory lectures on cells of the immune system and inflammation.,3. The Macrophage Home Page http:/www.path.ox.ac.uk/sg A recently updated introduction to the cells of the mononuclear phagocyte family.?4. Antigen Presentation http:/ A nice introduction to antigen presentation, part of Kimballs Biology Pages. ? 5. Clinical and basic Immunology tutorials http:/.au/davidful/Net_Path_Immunology/tutes.html,
