Connective Tissue and Joints Flashcards
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.
AIRE
- autoimmune regulator.
- induces self antigen expression.
- mutation ⇒ autoimmune polyendocrinopathy.
Peripheral Tolerance
- via anergy, suppression by regulatory T cells, deletion by activation-induced cell death, or antigen sequestration.
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.
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).
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.
Antigen Sequestration
- immune-privileged sites that have an impermanent blood-tissue barrier.
- ex. eye, testis, brain.
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.
NOD-2
- part of sensing mechanism for intracellular microbes.
- mutation ⇒ exaggerated inflammation in resonse to normal GI flora.
- implicated in inflammatory bowel disease.
IL-2 and IL-7 Receptor
- mutation ⇒ affects regulatory T cell development and maintenance.
- in multiple sclerosis.
Molecular Mimicry
- microbe sharing epitopes with self antigens could cross-react ⇒ damage normal tissues.
Role of Infection in Autoimmune Disorders
- through molecular mimicry
- tissue injury ⇒ structurally alter self antigens or release normal self antigens ⇒ activate T cells.
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.
TH1 Responses
- macrophage rich inflammation and substantial Ab-mediated elements.
TH17 Response
- neutrophil-mediated injury.
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.
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.
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.
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.
Lupus Joints
- nonspecific, nonerosive synovitis with minimal joint deformity.
Lupus CNS
- neuropscyh manifestations from damage to endothelium and antiphospholipid antibodies or impaired neural function from autoantibodies to synovial membrane antigen.
Lupus Serositis
- ex. pericarditis.
- initially fibrinous with focal vasculitis, fibrinoid necrosis, and edema ⇒ adhesions obliterating serosal cavities.
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.
Lupus Spleen
- splenomegaly with capsular thickening and follicular hyperplasia.
- penicilliary artery perivascular fibrosis ⇒ onion-skin appearance.
Lupus Lungs
- pleuritis and/or effusions in 50%.
- chronic interstitial fibrosis and 2° pulmonary HTN.
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.
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
Mikulicz Syndrome
- lacrimal and salivary gland enlargement from any cause.
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.
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.
Scleroderma Alimentary Tract
-
progressive atrophy and fibrosis of muscularis
- esophagus = rubber-hose consistency.
- mucosal thinning, ulceration, scarring.
Scleroderma Musculoskeletal System
- inflammatory synovitis ⇒ fibrosis.
- muscle involvement begins proximally with edema and mononuclear perivascular infiltrates ⇒ interstitial fibrosis with myofiber degeneration
Scleroderma Kidney
- affected in 2/3 pts.
- 50% of deaths from renal failure.
- intimal proliferation and deposition of mucinous or collagenous material in vessel walls.
- HTN ⇒ fibrinoid necrosis with thrombosis and necrosis.
Scleroderma Lungs
- variable fibrosis of small pulmonary vessels with diffuse interstitial and alveolar fibrosis ⇒ honeycombing
Scleroderma Heart
- perivascular infiltrates with interstitial fibrosis ⇒ restrictive cardiomyopathy or arrhythmias
Mixed Connective Tissue Diseases
- subgroup of autoimmune diseases.
- can evolve into SLE or scleroderma.
- characterized by:
- high Ab titers to U1 ribonucleoprotein
- modest initial renal involvement
- good initial response to steroids
- complications = pulmonary HTN, progressive renal disease.
Direct Pathway of Allograft HLA Recognition by Host T cells
- host T cells recognize donor HLA on donor derived APC, usually donor dendritic cells.
- CD8+ cells recognize HLA type I ⇒ CTL
- CD4+ cells recognize HLA type II ⇒ TH1 and TH17.