autoantibodies ’ clinical significans
TRANSCRIPT
Autoantibodies – Clinicalsignificans
Marečková H., Malíčková K., Janatková I., Fučíková T.
Institute of Immunology and Microbiology, 1st Medical Faculty, Charles University
Autoimmunity
Immunopathological process giving rise to unregulated immune response to autoantigens
AntibodiesHorror autotoxicus natural antibodies
1901 present
Autoantibodies – role in diseases
• Protective – polyreactive naturalantibodies, mostly IgM isotype, react withboth self and non-self antigens
• Pathogenic – cytotoxic, immune complex, regulatory autoAb
Autoantibodies – clinical significans
Diagnostic
pathogenic role – known, hypothesis, unknown
Predictive
Unknown
Antibodies
• Organ specific - endocrinopathies
• Organ nonspecific - SLE
Disease specific – AAV
Disease associated – Crohn´s disease
Predictive antibodies
• Markers of future disease in presently healthyindividuals
• anti CCP – was found years before onset ofdisease (median 4-5 years)
• Neonatal lupus – most of mothers are healthy atthe time of delivery – SLE and Sjogren sy later
• Anti GAD, anti insulin, anti islet cells – presence of two of them is highly correlated withprogression to overt diabetes – intervation trials
Diagnosis of autoimmune disease
• Clinical symptoms – common (fatigue, subfebrile or febrile) – signs of organ damage
• Inflammatory markers – ESR, CRP, leucocytosis
• Nespecific immunological tests –immunoglobulins, complement
• Antibodies – clustering with clinicalsymptoms
Renal autoimmunity• AAV – ANCA associated vasculites
c-ANCA - Wegener´s granulomatosisp-ANCA - Churg-Strauss syndrome
Goodpasture´s syndrome – anti GBM
Prosím anti GBM
Systemic lupus erythematodeslaboratory criteria- positive ANAb- positive anti ds DNA or anti Sm or aCL (LA)
Endocrine system
• Thyroid diseases. Addison´s disease• Diabetes mellitus – predictive autoAb
Islet cell antibodies – anti GAD 65 – glutamic acid decarboxylase
- IA -2 – member of transmembrane protein tyrosine
phosphatase family
Insulin
Nervous system
• Myastenia gravis – anti AChR Ab• anti striated muscles Ab• Paraneoplastic syndrome –
Against cytoplasma of cerebellar Purkinje cells - anti Yo antibodies
Anti neuronal nuclear antibody (ANNA) – anti Ri, anti Hu
Gastrointestinal tract
• Idiopathic bowel diseases• Coeliac disease– anti endomysial Ab• - anti tissue transglutaminase• - anti gliadin Ab
Silent coeliac disease – co-existence with other autoimmune disorder
Liver diseases
• Autoimmune hepatitis – LKM 1-3, ANAb• Primary biliary cirhosis – AMAb – M2 pattern
Antibody clusteringAutoantibodies cluster with distinct clinical
phenotypes
Scleroderma – ACA are strongly associatedwith the slowly progressive, limited andintermediated cutaneous subsets – antitopoisomerase I and anti RNA polymerase I/III cluster with more rapidlyprogressive and diffuse form ofcutaneous form
The pathogenic role of autoantibodies to nuclearautoantigens in systemis sclerosis, Senecal, 2005
Antibody clustering and SLE
• Cluster 1 – anti Sm, anti RNP (n = 451)• Cluster 2 – anti ds DNA, anti Ro, anti La (n=
470)• Cluster 3 - anti ds DNA, LAC and aCL (n=436)
Is antibody clustering predictive of clinical subsetsand damage in SLE? C.H. To, M Petri ,2005
C 1 – lowest incidence of proteinuria, anemia, lymphopenia and thrombocytopenia
lower incidence of nephrotic syndrome and leukopenia (2)
C 2 – highest female to male ratio, more patients with secondary SSsy
C 3 – highest incidence of arterial thrombosis, venous thrombosis, livedo reticularis
Anti ds DNA Ab and lupus nephritis
• Anti ds DNA antibodies and apoptoticnucleosomes may form immunecomplexes intra glomerularly
Anti ds DNA Ab and lupus nephritis. Rekvig O.P., 2004
Anti ds DNA crossreact with non-DNA kideny antigens pressent in glomeruli
Anti DNA Ab and SLE
• Anti ds DNA antibodies may penetrate intoliving cells (glomerular cells, renal tubularcells, hepatocytes, neuronal cells, fibroblasts and mononucclear cells)
• Cross-reactive bind to cytoplamic or intranuclear target• Linked to both cell proliferation and cytotoxicity• Binding can upregulate inflammatory pathways
New approches to the renal pathogenicity of anti DNA antibodiesin SLE , Putterman, 2004
Autoantibodies – Clinicalsignificans
• Positivity of autoantibody is not enough fordiagnosis of autoimmune disease
• Positivity of antibodies can cluster withdistinct clinical phenotypes
• Positivity of autoantibody (diseasespecific) could predict autoimmunedisease several years before onset
• Positivity of autoantibody (speciallyantinuclear) is motive for monitoring ourpatient – tendency to autoimmune reaction