Tuesday, March 6 (ellen)

Review Type 1-4 Hypersensitivity Reactions SLE ~ multiple genetic markers for lupus  different manifestations of the disease ~ often relapse symptoms ~ epidemiological trends – black America females of child bearing age ~ hormonally influenced? Not age related ~ improvement with pregnancy? ~ skin m/c affected, organs, blood cells, KI damage (often cause of death) ~ Antiphospholipid antibody ~ get hemorrhage and lack of clotting ~ in vitro – lack clotting, in vivo – tend towards thrombosis ~ potential cause of miscarriage (thrombosis in placenta) ~ “antiphospholipid antibody syndrome” – has had a thrombotic event AND presence of Ab ~ can have this dx without lupus as primary diagnosis ~ correlated to endothelial damage (usually precedes development of thrombosis) ~ antinuclear Ab ~ run ANA titre  not very specific, can be to histones, chromatin, RNA, etc ~ sensitive but not specific, very little false positives ~ see certain patterns that are more specific to lupus – speckled pattern ~ 25% monozygotic twins have lupus together ~ might have something to do with complement deficiencies  Antigen sticks around longer and may cause immune complexes to attack self along with Ag that are on “Self cells” ~ overactive T and B cells  responds to something that it shouldn’t be responding to ~ increase number of B cells ~ increased responsiveness to cytokines that are secreted by T helper cells  causing more B cell production  causing more Ab ~ skewed to CD4 T helper cell family (CD4 secrete cytokines when it sees Ag, and cytokines activate all other aspects of immune system to facilitate process) ~ genetic susceptibility to lupus may have increase in 6 hydroxy-estrogen ~ take home message: there IS hormonal influence ~ infections agents always suspect in autoimmune diseases as a trigger ~ Type II and III involved in lupus ~ immune complex related in KI failure ~ autoAb destroy endothelial cells, get fibrosis, inflammatory leukocyte tries to patch up blood vessel and then get lumen narrowing ~ causes acute necrotizing vasculitis ~ antiphospholipid Ab  increase hypercoagulability of blood, makes this situation worse ~ skin conditions are worse with UV exposure ~ there are immune complexes at dermoepidermal junction ~ characteristic butterfly rash

~ often involve serosal layers ~ affect heart and lungs ~ pericarditis ~ valvular abnormalities, caused by fibrous tissue (that’s trying to repair damage to endothelial layer) ~ see stenosis or regurgitation ~ Libman-Sacks – non bacterial verrucous endocarditis ~ more common before treatment with corticosteroids ~ coronary artery disease ~ thrombosis, damage to epithelium, often HTN (due to KI damage) ~ joints ~ mononuclear infiltration of synovial membrane ~ not really a big problem, it’s not erosive, just painful (arthralgia) ~ a bit of swelling ~ CNS ~ endothelial injury  intimal proliferation  microinfarcts  nerologic deficit ~ may have autoAb against synaptic structure ~ spleen ~ splenomegaly  fibrosis of arteries and capsule of SP  general decreased function  enlarged ~ get immune system complex deposition in SP (should remove damaged immune cells in body, cause SP to be overactive when there’s so many damaged immune cells) ~ serosal membranes ~ effusions  fibrinous exudates  opacification (white on CXR) ~ KI disease – m/c cause of death ~ KI trying to filter out immune complexes, but these get wedged in the small area in the KI and then get inflammation  proliferation of endothelial cells  necrosis  scarring  hematuria, proteinuria ~ most severe and common type  diffuse proliferative glomerulonephritis ~ severity really depends on genetic susceptibility ~ in diffuse proliferative GN and membranous GN can see nephrotic syndrome – not filtering as much as you should  get more protein escaping  see edema, ascities Rheumatoid Arthritis ~ no infectious process that’s making joints worse ~ still see systemic chronic inflammation – but NON supporative ~ there is extra articular involvement ~ may be infectious stimulant, maybe an organism causing the immune system to kick in ~ there isn’t an infection IN the joint, just that the immune system kicks in and makes the rheumatoid arthritis worse ~ in Europe and Northern Africa have more ~ multiple genes involved ~ HLA DR4/DR1 ~ may be specific to joint tissue ~ if there’s an Ag present, then activate T-helper cells, activate cytokines, macrophages, B-cells in joint  inflammation, antibody production

~ type 4 hypersensitivity, not Ab mediated, it’s cell mediated ~ Rheumatoid factor (in 80% of those with RA) ~ IgMs against IgGs ~ immune complexes developed  see tissue damage  subQ nodules ~ extra articular manifestations are more Ab mediated ~ joint damage ~ CD4 activates plasma cells and cause macrophage infiltration ~ synovial cell proliferates and you get hyperplasia ~ neutrophil activation and fibrin deposition in joint space with proteolytic enzymes = PANNUS ~ see proteolytic enzyme secretion  periarticular edema  activate osteoclast around joint by cytokines in area  erosion of bone and cartilage  osteopenia, joint fibrosis and calcification  ankylosis (linking of 2 bones and they fuse), bony deformities ~ extra-articular manifestations ~ mediated by rheumatoid factor ~ subcutaneous nodules ~ fibrinoid necrosis surrounded by macrophages and granulation tissues ~ nodule tries to contain the immune complex ~ often forms in pressure points (ex: elbows), or viscera ~ also see vasculitis, serositis, uveitis, keratoconjunctivitis  all depends on genetic susceptibility Scleroderma ~ fibrosis of body tissues ~ middle aged women ~ diffuse – widespread skin involvement, rapid progression ~ limited – slow progression, minimal skin involvement ~ CREST syndrome – calcinosis, Raynaud phenomenom, esophageal immotility, sclerodactly, telangectasia ~ Ag accumulate in area  endothelial injury  CD4 activation  cytokines get secreted  activate B cells, mast cells, and macrophage  these secrete fibrogenic cytokines (IL-1, TNF, etc)  get fibroblast activation  see excessive fibrotic tissue ~ see antinuclear Ab (ANA)  see anti-Scl 70 (common but not definitive? Acts as markers) ~ 90% of patients have skin involvement ~ edema from infiltration of immune cells, see microvascular disease ~ there’s fibrosis of derma, atrophy of appendages, limited ROM, cutaneous ulceration, tightening of skin, Raynaud’s ~ 90% have GIT problems ~ atrophy and fibrosis of muscularis  affects peristalsis and swallowing ~ strictures in esophagus, malabsorption (atrophy of the microvilli in small intestine) ~ LU (50%) ~ pulmonary fibrosis and endothelial damage ~ see pulmonary HTN  HT problems  R sided congestive HT failure  cor pulmonale

~ KI (66%) ~ thickening of vessel walls of interlobular arteries (in lupus, the KI has immune complex deposition which is type III) ~ HTN in KI  Renal stenosis  HTN in body ~ MSK ~ synovial hyperplasia and inflammation  fibrosis (no PANNUS formation as in RA, no proteolytic enzymes that cause the destruction) Sarcoidosis ~ see non-caseating granulomas ~ caseating granuloma is “cheesy”, so can’t ddx in CXR, need biopsy ~ will see granuloma in CXR in TB, CA, cystic fibrosis ~ t cell dysregulation ~ diagnosis of exclusion ~ see systemic systems  weakness, fatigue, spontaneous sweating, SOB, cough ~ little consistency in tests ~ see HLA association ~ progressive chronicity OR remission/relapse ~ possible microbial activation  see accumulation of CD4  which means less CD8 (cytotoxic)  increased TH1 (Ab production and inflammation) and other inflammatory cytokines  macrophage activation  collection of epitheliod histiocytes (mononuclear phagocytes) rimmed by CD4  epitheliod non-caseating granuloma  proliferation of fibroblasts  scarification ~ mainly LU problem Restrictive, pulmonary HTN ~ get bilateral hilar and peripheral lymphadenopathy (firm and hard – mimic CA) ~ in skin  erythema nodosum, granulomas, plaques ~ may affect eye, lacrimal gland, parotid gland, splenomegaly, hepatomegaly