1. AUTOIMMUNITY- III

2. Autoimmunity Part-III l At the end of the session the student should be able to: l a. Describe the pathogenesis of important autoimmune disorders: l 1) SLE. l 2) Rheumatoid arthritis. l 3) Sjogren’s syndrome etc. l Suggested readings: Robbins basic pathology, 8th edition. Page:139 - 152

3. Diagnostic criteria for autoimmune diseases l Three requirements should be met: l (1) Presence of an immune reaction specific for some self-antigen or self-tissue. l (2) Evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance. l 3) Absence of another well-defined cause of the disease.

4. How to establish the Diagnosis l History: characteristic symptoms l Classical physical findings and signs l Imaging& Laboratory studies: »Radiological »General: UG, CBC, ↑ESR, ↑CRP, RF »Hormonal assay »? HLA »Renal and skin biopsy – H&E + IF »Auto-antibodies Screening (serology, IF)

5. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) l SLE- a multisystem disease of autoimmune origin, characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs). l SLE predominantly affects women. l SLE manifest in any age even early childhood l Clinical presentation: l complex of criteria approved by (American society of rheumatology), different presentation. Acute or insidious in its onset, chronic, remitting and relapsing. l febrile illness, injury to the skin, joints, kidney, and serosal membranes. other organ in the body,

6. SLE- Pathogenesis l The cause of SLE remains unknown. l SLE—both documented and postulated—are as varied and complex l The pathogenesis: l 1) Genetic factors. l 2) Immunological factors l 3) Environmental factors. l Outcoms l Antibodies against self-constituents (SM, Nuclei, Nucleoli, DNA)due to a failure of the mechanisms that maintain self-tolerance.

7. SLE- Pathogenesis 1) Genetic susceptibility. contributions from MHC and multiple non-MHC genes l Evidence support a genetic predisposition: l a) Family history- increased risk.1 st degree. l b) Monozygot twins – higher rate l c) Studies of HLA associations- HLA-DQ locus > produce Anti-sm, DNA, Phospholipid. l d) Inherited deficiencies of early complement components, such as C2, C4, or C1q.>> impair removal of circulating immune complexes& Tissue deposition+ loss of B tolerance.

8. SLE- Pathogenesis l 2) Immunological Factors: a) Defective elimination of self-reactive B cells b) Escape tolerance CD4+ helper T cells specific for nucleosomal antigens>production autoantibodies. c) Nuclear DNA and RNA contained in immune complexes may activate B lymphocytes. d) The role of cytokines (interferons-1, TNF), release as response to Viral infection lead to >> activate dendritic cells, B cells& promote T H 1 responses>production of autoantibodies.

9. SLE- Pathogenesis l 3) Environmental Factors: a) Exposure to ultraviolet (UV) light exacerbates SLE>> induce enhance inflammation, apoptosis & alter the DNA >> Immunogenic. a) Sex hormones> exert an important influence on the occurrence and manifestations of SLE. b) Drugs such as hydralazine, procainamide, and D- penicillamin > induce an SLE-like response.

16. Rheumatoid arthritis l RA- defined as autoimmune disease (multi- systemic, non-organ specific) with Articular & Extra-articular manifestations. l Articular lesion- chr. by Non-suppurative proliferative synovitis, which leads to destruction of articular cartilage >> Lead to progressive disabling arthritis. l Extra-articular manifestation may strongly resemble SLE or scleroderma- such as the skin, blood vessels, lungs, and heart. l Age: Usual onset in decades 4 and 5 l Sex: 3-5X more common in women than in men

19. Rheumatoid arthritis l Etio-Pathogenesis: l precise trigger which initiates destructive immune response is not known l Specificity of Pathogenic T Cells: Unknown antigen in joint synovium (type II collagen?); role of antibodies ? l 1- Genetic susceptibility l 2- Environmental arthritogen l 3- Immunological factor

20. Rheumatoid arthritis-Pathogenesis l 1- Genetic susceptibility: l Non-HLA gene (PTPN22)> Tyrosine activity>> regulate and control T cell responses. l HLA-DRB1 associated with increased incidence of the inflammatory synovitis. l 2- Environmental arthritogen (implicated not proven) Smoking& infection(EBV,Proteus, M.tuberculosis). l 3- Immunological factors: l 3- 80% of +VE To RA factors (antibodies against Fc portion of IgG). l Initiated by activation of T-helper cells which produce cytokines and activate B cells to produce antibodies.

22. Rheumatoid arthritis l Clinical course »symmetrical, polyarticular arthritis »weakness, fever, malaise may accompany joint symptoms »stiffness of joints in AM early, then progresses to claw-like deformities »severely crippling in 15-20 years, life expectancy reduced 4-10 years. »Amyloidosis develops in 5%-10% of patients »Anemia of chronic disease present in late cases

23.  NORMAL Bi-Layered Synovium ↑ Destructive Rheumatoid Synovitis

24. Sjogren’s syndrome- SS l is a chronic Autoimmune disease chr. by Dry eyes (keratoconjunctivitis sicca) and Dry mouth (xerostomia) due to immune destruction of the lacrimal and salivary glands l Sicca syndrome - this phenomenon occurring as an isolated primary syndrome. l Extraglandular manifestations, such as cutaneous vasculitis,nephritis, etc… l Frequently associated with RA, some with SLE or other autoimmune processes.

25. Sjogren’s syndrome- SS l Etio-pathogenesis of SS - remains obscure l 1- Genetic- HLA gene: SS - associated with certain HLA alleles, HLA-DR3, HLA-B8,etc… l 2- Environmental factors : Viral infection of salivary glands “unclear relation”- e.g EPV HCV>> cells injury, death >> release self antigens>> B& T cell self activation. l The Primary target is ductal epithelial cells of exocrine glands, by chronic inflammatory infiltrates:CD4-T& B cells-plasma cells.

26. Sjogren’s syndrome-SS »Types of auto-antibodies : »75% of patient present with rheumatoid factor (an antibody reactive with self-IgG). » 50- 80% Presented with ANA. » 90% most have Ab against two ribo- nucleoprotein antigens anti -SS-A (R0) (early) and anti-SS-B (La) antibodies. The outcome: Salivary gland destruction, inflammation, fibrosis>>dry eyes + dry mouth

27. Sjogren’s syndrome l Clinical course »primarily in women > 50-60 »dry mouth, Nose-difficult swallowing solid diet, cracks, fissures, Lack of tears-Blurring vision, thick secretion »Salivary glands enlarged-50% parotid »EXTRANODAL manifestation: recurrent bronchitis, and pneumonitis, lung fibrosis, RA-synovitis » 1% develop lymphoma, 10% with pseudo- lymphomas »The combination of lacrimal & salivary gland inflammatory event called Mikulicz disease/ syndrome

30. Thanks