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Flashcards in Connective Tissue and Joints Deck (94)
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1

Central Tolerance

  • process by which B and T cells that recognize self antigens are either killed or rendered harmless.
  • autoreactive T cells can become regulatory T cells.
  • developing B cells that react to self antigen undergo Ig rearrangement = receptor editing.

2

AIRE

  • autoimmune regulator.
  • induces self antigen expression.
    • mutation ⇒ autoimmune polyendocrinopathy.

3

Peripheral Tolerance

  • via anergy, suppression by regulatory T cells,  deletion by activation-induced cell death, or antigen sequestration.

4

Anergy

  • type of peripheral tolerance.
  • irrversible functional inactivation when T cells don't receive co-stimulatory signals.
  • APC can inhibit T cells through T cell CTLA-4 or PD-1 receptors.
  • B cells lose capacity for antigenic stimulation with lack of T cell help.

5

Suppression by Regulatory T cells

  • type of peripheral tolerance.
  • regulatory T cells: CD4+, CD25, Foxp3 transcription factor ⇒ inhibit lymphocyte activation and function by secreting IL-10 and TGF-beta.
  • mutation in Foxp3 ⇒ severe autoimmune diseases = immune disregulation, polyendocrinopathy, enteropathy, X-linked (IPEX).

6

Deletion by Activation-Induced Cell Death

  • type of peripheral tolerance
  • persistent activation of self reactive T cells ⇒ increased expression of pro-apoptotic molecules or increased expression of FasL.
  • ↑ FasL ⇒apoptosis of T cells by engaging Fas.
  • B cells deleted by FasL positive T cells.
  • mutation in FAS ⇒ autoimmune lymphoproliferative syndrome.

7

Antigen Sequestration

  • immune-privileged sites that have an impermanent blood-tissue barrier.
    • ex. eye, testis, brain.

8

PTPN-22

  • encodes a tyrosine phosphatase.
  • mutation ⇒ doesn't counter activity of lymphocyte tyrosine kinases ⇒ excessive activation of lymphocyte tyrosine kinases.
  • implicatd in type I diabetes and rheumatoid arthritis.

9

NOD-2

  • part of sensing mechanism for intracellular microbes.
  • mutation ⇒ exaggerated inflammation in resonse to normal GI flora.
  • implicated in inflammatory bowel disease.

10

IL-2 and IL-7 Receptor

  • mutation ⇒ affects regulatory T cell development and maintenance.
  • in multiple sclerosis.

11

Molecular Mimicry

  • microbe sharing epitopes with self antigens could cross-react ⇒ damage normal tissues.

12

Role of Infection in Autoimmune Disorders

  • through molecular mimicry
  • tissue injury ⇒ structurally alter self antigens or release normal self antigens ⇒ activate T cells.

13

Epitope Spreading

  • cryptic epitopes = epitopes within self antigens that aren't normally presented to T cells.
    • have no tolerance since never see the immune system.
    • when become exposed can ⇒ persistent autoimmunity.

14

TH1 Responses

  • macrophage rich inflammation and substantial Ab-mediated elements.

15

TH17 Response

  • neutrophil-mediated injury.

16

Systemic Lupus Erythematosus (SLE)

  • autoimmune disorder.  9:1 females:male.
  • Abs:  ANA, anti-dsDNA, and anti-Smith.
    • 40-50% have antiphospholipid Abs.
    • may bind to cardiolipin ⇒ false positive for syphilis.
    • lupus anticoagulants = anticoagulant in vitro but procoagulant in vivo ⇒ vascular thromboses, miscarriages, and cerebral ischemia (secondary antiphospholipid Ab syndrome).
  • genetic predisposition
  • defective elimination of self reactive B cells and ineffective peripheral tolerance.
  • inappropriate B cell activation by nuclear RNA or DNA TLR 
  • environmental factors: UV light exacerbates SLE, estrogen, procainamide
  • pathogenesis:  cell injury ⇒ apoptosis and ↑ burden nuclear antigens.
    • defective B and T cell tolerance ⇒ autoantibodies to nuclear antigens ⇒ immune complexes in B cells and dendritic cells.
    • TLR engagement ⇒ cellular activation, cytokine production, augmented autoantibody synthesis ⇒ cell injury = self-amplifying loop.
  • tissue damage via immune complexes (type III hypersensitivity) or via Ab-mediated injury to blood cells (type II hypersensitivity).
  • morphology: involvement of skin, blood vessels, kidneys, CT.
    • see alterations in: kidney, skin, joints, CNS, pericarditis, cardiovascular system, spleen, and lungs.
  • presentation: systemic, chronic, recurrent, febrile illness particularly involving the skin, kidney, serosal membranes, and joints.
    • can have thrombocytopenia, leukopenia, and anemia.
    • characterized by recurrent flares and remissions.  
  • tx: immunosuppression.
  • death usually from renal failure or intercurrent infection.

17

Lupus Kidney

  • almost always involved.
  • injury from immune complex deposition.
  • 5 patterns of lupus nephritis with increasing degrees of cellular infiltration, microvascular thrombosis, and vascular wall deposition.
  • ⇒ varying degrees of hematuria, proteinuria, HTN, and renal insufficiency.

18

Lupus Vessels

  • type III hypersensitivity with acute necrotizing vasculitis and fibrinoid deposits involving small arteries and arterioles.
  • Ig, dsDNA, C3 in vessel walls.  perivascular lymphocytic infiltrate.
  • chronic = fibrous thickening and lumenal narrowing.

19

Lupus Skin

  • classic = malar erythema.
  • exacerbated by sunlight.
  • basal layer degeneration with dermal-epidermal junction Ig and complement deposits.
  • dermis has variable fibrosis, perivascular mononuclear cell infiltrates, and vascular fibrinoid change.

20

Lupus Joints

  • nonspecific, nonerosive synovitis with minimal joint deformity.

21

Lupus CNS

  • neuropscyh manifestations from damage to endothelium and antiphospholipid antibodies or impaired neural function from autoantibodies to synovial membrane antigen.

22

Lupus Serositis

  • ex. pericarditis.
  • initially fibrinous with focal vasculitis, fibrinoid necrosis, and edema ⇒ adhesions obliterating serosal cavities.

23

Lupus Cardiovascular System

  • pericarditis, myocarditis.
  • classic = nonbacterial verrucous (Libman-Sacks) endocarditis.
    • small warty vegetations on inflow/outflow of mitral/tricuspid valves.
    • can have diffuse leaflet thickening of mitral/aortic valves ⇒ functional stenosis or insufficiency.
  • ↑ incidence of accelerated coronary atherosclerosis from exacerbated risk factors (HTN, hypercholesterolemia) and antiphospholipid Ab-mediated vascular damage.

24

Lupus Spleen

  • splenomegaly with capsular thickening and follicular hyperplasia.
  • penicilliary artery perivascular fibrosis ⇒ onion-skin appearance.

25

Lupus Lungs

  • pleuritis and/or effusions in 50%. 
  • chronic interstitial fibrosis and 2° pulmonary HTN.

26

Chronic DIscoid Lupus Erythematosus

  • cutaneous lesions that mimic SLE
  • 35% have positive ANA
  • deposition of Ig and C3 at dermal-epidermal junction
  • 5-10% develop systemic manifestations.

27

Sjögren Syndrome

  • characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) from immune-mediated lacrimal and salivary gland destruction.
  • mostly women btw 35-45yrs.
  • 40% are primary syndrome, rest are in association with autoimmune disease (RA most common but also SLE and scleroderma)
  • can have RF, ANAs to ribonucleoproteins SS-A and SS-B
  • injury started by CD4+ T cells to unknown self antigen.
  • EBV and Hep C may be involved as well as HTLV-1
  • morphology: initially periductal lymphocytic infliltrate with ductal epithelial hyperplasia and luminal obstruction.
    • then acinar atrophy, fibrosis, and fatty replacement.  lymphoid infiltrate can make lymphoid follicles and germinal centers.
    • can have corneal inflammation, erosion, and ulceration.
    • atrophy of oral mucosa with inflammatory fissuring and ulceration
    • have nasal drying and crusting, potentially septal perforation.
    • respiratory involvement laryngitis, bronchitis, or pneumonitis.
  • presentation: difficulty swallowing food, vision changes.
    • 1/3 have synovitis, pulmonary fibrosis, peripheral neuropathy.
    • renal tubular acidosis and phosphaturia with tubulointerstitial nephritis.
    • adenopathy with pleomorphic lymph node infiltrate ⇒ ↑ risk B-cell lymphoma.
  • dx: lip biopsy

28

Mikulicz Syndrome

  • lacrimal and salivary gland enlargement from any cause.

29

Scleroderma

  • characterized by widespread vascular injury and progressive perivascular/interstitial fibrosis in multiple organs.  skin, GI, kidneys, heart liver, lung.
  • 3:1 f:m ratio, peak ages 50-70yrs.
  • diffuse scleroderma = widespread skin involvement, rapid progression, early visceral involvement.
  • limited scleroderma = limited cutaneous involvement, late visceral involvement, benign course.
    • can develop calcinosis, Raynaud's, esophageal dysmotility, sclerodactyly, telangiectasia, or CREST syndrome.
  • CD4+ T cells respond to unknown antigens and release TGF-beta and IL-13 to activate inflammatory cells and fibroblasts.
    • markers: antitopoisomerase I (in scleroderma and pulm fibrosis); anticentromere (CREST syndrome)
  • hallmark = microvascular injury from direct autoimmune attack or by-product of chronic perivascular inflammation
    • cycles of endovascular injury with platelet aggregation ⇒ vascular smooth muscle and fibroblast proliferation, matrix synthesis ⇒ narrowing
  • fibrosis from ischemic scarring and fibrogenic cytokine elaboration and hyperresponsiveness of fibroblasts to growth factors.
  • morphology:  affects skin, alimentary tract, musculoskeletal system, kidneys, lungs, heart.
  • presentation: cutaneous fibrosis, Raynaud's phenomenon, dysphagia, malabsorption/intestinal pain/obstruction, pulmonary fibrosis ⇒ respiratory or right-sided heart failure, arrhythmias, malignant HTN ⇒ renal failure.

30

Scleroderma Skin

  • diffuse sclerosis with atrophy
  • initially edematous with doughy consistency
  • face = drawn mask
  • fingers = fibrotic, tapered and clawlike with diminished motility.
  • focal vascular obliteration ⇒ ulceration.
  • fingertips may auto-amputate.