Connective Tissue and Joints Flashcards
1
Q
Central Tolerance
A
- 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
Q
AIRE
A
- autoimmune regulator.
- induces self antigen expression.
- mutation ⇒ autoimmune polyendocrinopathy.
3
Q
Peripheral Tolerance
A
- via anergy, suppression by regulatory T cells, deletion by activation-induced cell death, or antigen sequestration.
4
Q
Anergy
A
- 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
Q
Suppression by Regulatory T cells
A
- 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
Q
Deletion by Activation-Induced Cell Death
A
- 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
Q
Antigen Sequestration
A
- immune-privileged sites that have an impermanent blood-tissue barrier.
- ex. eye, testis, brain.
8
Q
PTPN-22
A
- 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
Q
NOD-2
A
- part of sensing mechanism for intracellular microbes.
- mutation ⇒ exaggerated inflammation in resonse to normal GI flora.
- implicated in inflammatory bowel disease.
10
Q
IL-2 and IL-7 Receptor
A
- mutation ⇒ affects regulatory T cell development and maintenance.
- in multiple sclerosis.
11
Q
Molecular Mimicry
A
- microbe sharing epitopes with self antigens could cross-react ⇒ damage normal tissues.
12
Q
Role of Infection in Autoimmune Disorders
A
- through molecular mimicry
- tissue injury ⇒ structurally alter self antigens or release normal self antigens ⇒ activate T cells.
13
Q
Epitope Spreading
A
-
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
Q
TH1 Responses
A
- macrophage rich inflammation and substantial Ab-mediated elements.
15
Q
TH17 Response
A
- neutrophil-mediated injury.
16
Q
Systemic Lupus Erythematosus (SLE)
A
- 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
Q
Lupus Kidney
A
- 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
Q
Lupus Vessels
A
- 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
Q
Lupus Skin
A
- 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
Q
Lupus Joints
A
- nonspecific, nonerosive synovitis with minimal joint deformity.
21
Q
Lupus CNS
A
- neuropscyh manifestations from damage to endothelium and antiphospholipid antibodies or impaired neural function from autoantibodies to synovial membrane antigen.
22
Q
Lupus Serositis
A
- ex. pericarditis.
- initially fibrinous with focal vasculitis, fibrinoid necrosis, and edema ⇒ adhesions obliterating serosal cavities.
23
Q
Lupus Cardiovascular System
A
- 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
Q
Lupus Spleen
A
- 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**.
31
**Scleroderma Alimentary Tract**
* **progressive atrophy and fibrosis of muscularis**
* **esophagus = rubber-hose consistency.**
* **mucosal thinning, ulceration, scarring.**
32
**Scleroderma Musculoskeletal System**
* **inflammatory synovitis ⇒ fibrosis**.
* muscle involvement begins **proximally with edema and mononuclear perivascular infiltrates ⇒ interstitial fibrosis with myofiber degeneration**
33
**Scleroderma Kidney**
* affected in **2/3 pts**.
* **50% of deaths from renal failure**.
* i**ntimal proliferation and deposition of mucinous or collagenous material in vessel walls.**
* HTN ⇒ **fibrinoid necrosis** with thrombosis and necrosis.
34
**Scleroderma Lungs**
* variable fibrosis of small pulmonary vessels with **diffuse interstitial and alveolar fibrosis ⇒ honeycombing**
35
**Scleroderma Heart**
* perivascular infiltrates with interstitial fibrosis ⇒ **restrictive cardiomyopathy or arrhythmias**
36
**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.**
37
**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.
38
**Indirect Pathway** of Allograft HLA Recognition by Host T cells
* **host T cells recognize donor HLA through host APC**.
* ⇒ DTH mediated by CD4+ cells.
39
**Hyperacute Rejection**
* recipient **previously sensitized to graft antigens** (blood transfusion or pregnancy).
* **circulating Ab binds graft HLA ⇒ immediate complement and antibody dependent cell-mediated cytotoxicity injury**.
* occurs within **minutes to days.**
* organ looks **cyanotic, mottled, and flaccid**.
* resembles immune-complex mediated disease: complement and Ig in vessel walls ⇒ **endothelial injury, fibrin-platelet microthrombi, neutrophil infliltrates, and arteriolar fibrinoid necrosis** ⇒ distal parenchymal infarction.
40
**Acute Rejection**
* **days to months** after transplantation or cessation of immunosuppressive therapy.
* **_acute cellular rejection_** = **interstitial mononuclear cell infiltrate** (macrophages, CD4+, CD8+)
* **_acute humoral rejection_** = rejection vasculitis. **newly made anti-donor Ab ⇒ necrotizing vasculitis with thrombosis**
* **complement C4D deposition** in vascular beds = diagnostic feature.
* **_subacute vasculitis_** = **intimal thickening** from proliferating fibroblasts, smooth muscle cells, and macrophages** ⇒ vascular narrowing and infarction.**
41
**Chronic Rejection**
* **months to years**.
* progressive organ dysfunction.
* **dense obliterative intimal fibrosis ⇒ allograft ischemia**.
42
**Means to Increase Graft Survival**
* HLA matching
* immunosuppressive therapy blocking T cell activation or co-stimulation, IL-2 production, signaling, T cell proliferation, and inflammation.
* T cell destruction
* Plasmapheresis or anti-B cell therapy
43
**Hematopoietic Cell Transplants**
* for hematologic malignancies, aplastic anemia, or immunodeficiency states.
* complications = **recipient NK cells or radiation resistant T cells, Graft versus Host Disease.**
44
**Graft Versus Host Disease (GVHD)**
* **donor lymphocytes recognize host cells as foreign** ⇒ CD4+ and CD8+ mediated injury.
* mostly **affects host immune cells** (immunosuppression), **biliary epithelium** (jaundice), **skin** (desquamative rash), and **GI mucosa** (bloody diarrhea)
45
**Noninfectious Inflammatory Myopathies**
* **immune mediated** disorders characterized by **skeletal muscle inflammation and injury**.
* **dermatomyositis**
* **polymyositis**
* **inclusion body myositis**
46
**Dermatomyositis**
* **skin and muscle.**
* **targets capillaries**.
* **lilac discoloration** of upper **eyelids** and periorbital edema with weakness
* **scaling, erythematous patches** over knuckles, elbows, and knees (**Grotton lesions**).
* **weakness in proximal muscles** first, **bilaterally symmetric**.
* **dysphagia** in 1/3 pts.
* can have interstitial lung disease, vasculitis, and myocarditis.
* **1/4 adults with this have cancer**.
* **kids have GI symptoms**, 1/3 have **calcinosis**.
* _morphology_: **perivascular inflammatory infiltrates** with **scattered necrotic muscle fibers muscle fiber atrophy** = **perifascicular atrophy**
* tx: immunosuppression
47
**Polymyositis**
* mostly in **adults**.
* **bilateral muscle weakness starting in proximal muscles**.
* **cytotoxic T-cell driven** myocyte damage
* **auto-Ab against tRNA synthetases**.
* **morphology**: **endomysial inflammation, scattered necrotic muscle fibers**, no vascular injury
* tx: immunosuppressive therapy
48
**Inclusion Body Myositis**
* **begins with distal muscle involvement** (extensors of knee, flexors of wrist).
* can be **asymmetric**
* **insidious onset**, **age \>50yrs**.
* frequently have **intracellular deposits of beta-amyloid and hyperphosphorylated tau proteins** = abnormal protein folding.
* not helped by immunosuppression.
* _morphology_: endomysial inflammatory infiltrates are **rimmed vacuoles** = **clear cytoplasmic vacuoles in myocytes surrounded by thin rim of basophilic material.**
* may have amyloid deposits on Congo red stain.
49
**Immune-Complex Associated Vasculitis**
* **deposition of circulating antigen-Ab complexes ⇒ complement activation and recruitment of Fc receptor-bearing cells**.
* see with drug hypersensitivity, viral infections.
50
**MPO-ANCA**
* aka **p-ANCA**.
* Ab against MPO.
* see in **microscopic polyangiitis** and **Churg-Strauss syndrome**
51
**PR3-ANCA**
* aka **c-ANCA**.
* against a neutrophil azurophilic granule constituent.
* in **Wegener granulomatosis**
52
**Anti-Endothelial Cell Ab**
* see in **Kawasaki disease**
53
**Giant Cell (Temporal) Arteritis**
* **most common vasculitis** in USA
* **focal granulomatous inflammation** of **med and small arteries**
* **temporal arteries**
* involve aorta = **_giant cell aortitis_**
* **T cell mediated** immune response to vessel wall antigens.
* _morphology_: **granulomatous vasculitis** with **elastic tissue fragmentation**, **multinucleated giant cells, intimal fibrosis** with **medial scarring** and **luminal narrowing**.
* _presentation_: **headache and facial pain**. may have flu-like symptoms with fever, fatigue, weight loss.
* **ophthalmic artery** involved ⇒ visual problems and potential **blindness**.
* _tx_: steroids
54
**Takayasu Arteritis**
* aka **pulseless disease**.
* **granulomatous** vasculitis of **med and large arteries**
* **transmural fibrous thickening of aortic arch** and **obliteration of great vessel branches**.
* _morphology_: **irregular aortic thickening** with **intimal hyperplasia**.
* a**dventitial perivascular mononuclear cell infiltrates ⇒ medial fibrosis, granulomas, acellular intimal thickening**.
* **indistinguishable from giant cell arteritis**.
* _presentation_: **eye and neuro disturbances**, weakening of upper extremity perfusion pressures (**weak or absent pulses**).
* involves **pulmonary artery** 50% of time.
* also in **coronary arteries and renal arteries**.
* **HTN** 2° to renal artery disease.
* **pt \<50yrs**.
55
**Polyarteritis Nodosa**
* necrotizing vasculitis of **small to med arteries. **
* involves kidney, heart, liver, and GI.
* 1/3 cases have immune complex deposition.
* _morphology_: **sharply demarcated** lesions.
* induce thrombus ⇒ **distal ischemic area**
* **temporal heterogeneity**.
* **_acute lesion_** = sharply circumscribed **arterial fibrinoid necrosis** (**hyaline** in vessel wall) with **neutrophilic infiltrates** into adventitia.
* **_healed lesion_** = marked **fibrotic thickening of artery with elastic lamina fragmentation and aneurysmal dilation**.
* _presentation_: **young adult** with **nonspecific systemic symptoms** (fever, malaise, weight loss) and presentation of **symptoms from organ involved.**
* _tx_: 90% remission with immunosuppressive therapy.
56
**Kawasaki Disease**
* **acute, febrile, self-limited illness of infants and kids**. associated with **med to large vessel arteritis.**
* T cell hypersensitivity.
* _morphology_: **sharply demarcated** lesions ⇒ thrombosis ⇒ distal ischemic injury.
* **_acute lesions_** = **arterial fibrinoid necrosis with neurophilic infiltrates.**
* **_healed lesions_** = fibrotic **thickening of artery with elastic lamina fragmentation and some aneurysmal dilation**.
* _presentation_: **fever, lymphadenopathy, skin rash, and oral/conjunctival erythema.**
* **20% ⇒ coronary arteritis** if untreated = aneurysms that rupture or thrombose ⇒ MI.
* _tx_: **aspirin and IV gamma globulin** to reduce incidence of coronary arteritis.
57
**Microscopic Polyangiitis**
* necrotizing vasculitis of vessels smaller than PAN (**arterioles, venules, and capillaries**).
* **temporal homogeneity**.
* most lesions **pauci-immune. p-ANCA** indicated.
* _morphology_: **fibrinoid necrosis** but vessel may show **leukocytoclastic vasculitis** (fragmented neutrophilic nuclei around vessels).
* **necrotizing glomerulonephritis and pulmonary capillaritis** common.
* Ig deposition rare.
* _presentation_: symptoms **depend on vascular bed**. include **hemoptysis**, **hematuria and proteinuria, purpura, or bowel pain and bleeding**.
* _tx_: cyclosporine and steroids.
58
**Churg-Strauss Syndrome**
* aka allergic granulomatosis and angiitis.
* **small vessel** necrotizing vasculitis associated with **asthma, allergic rhinitis, peripheral eosinophilia, and extravascular necrotizing granulomas**.
* **ANCAs in \<50%**.
* lesions resemble PAN but have eosinophils and granulomas.
* **60% develop cardiomyopathy** from eosinophils. causes mortality in 50%.
59
**Wegener Granulomatosis**
* triad of:
* **necrotizing or granulomatous vasculitis of small to med sized vessels in lungs and upper airway**
* **necrotizing granulomas of upper and lower respiratory tract**
* **glomerulonephritis**
* **c-ANCA** in 95%; T cell hypersensitivity
* _morphology_: **granulomas with geographic necrosis and vasculitis**;
* granulomas coalesce ⇒ nodules that **cavitate**
* renal lesions vary from **focal and segmental necrosis to proliferative GN**.
* _presentation_: **men \>40yrs**.
* 80% 1yr mortality without tx.
* _tx_: cyclophosphamide, steroids, TNF antagonist.
60
**Thromboangiitis Obliterans**
* aka **Buerger Disease**
* in **heavy smokers \<35yrs old**.
* segmental, thrombosing, acute, and chronic inflammation of **intermediate and small arteries and veins in extremities. **
* T cell hypersensitivity
* _morphology_: **acute lesions** = neutrophilic infiltrates with **mural thrombi with microabscesses**. **giant cell formation** and **involvement of adjacent vein and nerve**.
* **_late lesions_** organized and **recanalized**.
* _presentation_: consequences = **nodular phlebitis, Raynaud's, leg claudication**.
* vascular insufficiency ⇒ **pain at rest, skin ulcers, and gangrene**.
61
**Osteoarthritis**
* aka **Degenerative Joint Disease**
* **progressive erosion of articular cartilage**.
* **_primary DJD_** = insidious onset as age, in a few joints.
* knees and hands in women; hips in men
* **_secondary DJD_** = at any age in previously damaged joint or pts with diabetes, ochronosis, or hemachromatosis
* _pathogenesis_: **polymorphisms in PG synthesis and WNT signaling**. affected by **aging, obesity, muscle strenght, joint architecture**.
* phases:
* chondrocyte injury from age, trauma, biochemical/genetic influence.
* chondrocyte proliferation and secretion of matrix and inflammatory mediators ⇒ cartilage remodeling and changes in synovium/subchondral bone.
* chondrocyte dropout and cartilage loss from repetitive injury and chronic inflammation.
* _morphology_: articular surface soft with fragments of cartilage and subchondral bone (**joint mice**)
* **bone eburnation and sclerotic cancellous bone** underneath
* **cystic spaces** filled with synovial fluid
* **osteophytes capped by cartilage on edge of articular cartilage**.
* **Heberden nodes** = osteophytes of distal interphalangeal joints. mostly in women.
* **chondrocyte proliferation, ↑ matrix water, ↓ PG content** ⇒ fibrillation and cracking of matrix
* synovium congested with **scattered chronic inflammation**
* _presentation_: **insidious** and slowly progressive. **deep achy joint pain, worse with use, morning stiffness, crepitus, limited ROM**.
* osteophyte can ⇒ **radicular pain, muscle spasm or atrophy, and neurologic deficits**.
* no tx.
62
**Rheumatoid Arthritis**
* chronic systemic inflammatory disease of joints ⇒ **non-suppurative proliferative synovitis** ⇒ **joint destruction and ankylosis**
* can impact blood vessels, skin, heart, lungs, and muscles.
* **f:m 3-5:1. peak ages 40-70 yrs**
* _morphology_: affects joints, skin, and blood vessels.
* _joint_: **pannus** encroaches on hyaline cartilage ⇒ destruction. bridge btw bones ⇒ **fibrous ankylosis**.
* **hemosiderin deposits and aggregates of fibrin**.
* **bone erosion, osteoporosis, subchondral cysts**.
* _skin_: **rheumatoid nodules** found in knees, heart valves, lungs, spleen, aorta, and other viscera.
* **fibrinoid necrosis** with activated macrophages.
* _blood vessels_: high RF titers ⇒ **small to med vessel vasculitis**.
* _pathogenesis_: exposure to arthritogenic antigen ⇒ **loss of self-tolerance and chronic autoimmune response**.
* genetic: **HLA-DRB1; PTPN22** - tyrosine phosphatase regulating T cell activation.
* environmental: microbes (EBV, retroviruses, mycobacteria, Borrelia, Mycoplasma); modified host proteins.
* autoimmunity to type II collagen and glycosaminoglycans with TH1 and TH17 proliferation.
* **auto-Ab to citrulline-modified proteins**
* auto-Ab to Fc of IgG (**rheumatoid factor**)
* damage from IFN-gamma and IL-17 by producing IL-1, IL-6, IL-23, TGFbeta, PDE2 and **TNF**.
* _presentation_: non-specific malaise, fatigue, generalized pain ⇒ **insidious onset localized joint involvement**.
* **small joints first** (digits to wrist to ankles to elbows to knees).
* **bilaterally symmetric**
* **joints swollen, warm, painful.**
* greatest damage happens in first 5 years.
* destruction of tendons, ligaments, and joint capsules ⇒ r**adial deviation of wrist, ulnar deviation of fingers, flexion-hyperextension abnormalities of digits**
* **loss of joint stability and ROM**.
* joint effusions, **juxta-articular osteopenia, narrowing of joint space**.
* _tx_: corticosteroids, methotrexate, TNF antagonists
63
**RA Joint Morphology**
* **synovium edematous and hyperplastic** with delicate and bulbous **fronds**
* **pannus** of proliferative synovium, inflammatory cells, and fibroblasts encroach on hyaline cartilage ⇒ destruction
* bridges bones ⇒ **fibrous ankylosis** that can ossify
* lesions have dense **perivascular mononuclear infiltrate** with **focal lymphoid aggregates.**
* **neutrophils on synovial surface and in synovial fluid**.
* vasodilation and ↑ vascular permeability with **hemosiderin deposits and aggregates of fibrin**
* osteoclast activation with **bone erosion, osteoporosis, and subchondral cysts**
64
**RA Skin Morphology**
* **rheumatoid nodules**: **firm, non-tender** in subcutaneous tissues of **areas under recurrent pressure. (elbow)**
* in lungs, spleen, heart valves, aorta, other viscera.
* **central zone of fibrinoid necrosis** with palisade of **activated macrophages**.
65
**RA Blood Vessel Morphology**
* severe disease and high RF titers ⇒ **small to med sized vessel vasculitis**
66
**Juvenile Idiopathic Arthritis**
* 7 subsets of arthritis in **kids under 16yrs. persist at least 6 weeks**.
* differs from RA by:
* **oligoarthritis** more common, **systemic disease** more common, **large joints affected, ANA positive**, rheumatoid nodules not present.
* 10% ⇒ functional disability.
67
**Ankylosing Spondyloarthritis**
* aka Marie-Strümpell disease
* **chronic ankylosing synovitis of vertebrae and sacroiliac joints**.
* **m:f 2-3:1 with onset 20-30yrs**.
* progressive course involving **hips, knees, and shoulders. **
* complications = **uveitis, aortitis, and amyloidosis**
* 90% are **HLA-B27** positive
* also associated with **IL23 receptor** and **ARTS1** (codes a peptidase that trims peptides for HLA class I)
68
**Reiter Syndrome**
* **triad of arthritis, nongonoccocal urethritis or cervicitis, and conjunctivitis**.
* typically a 20-30yr old man.
* 80% have **HLA-B27**
* triggered by **prior GI or GU infection**. symptoms begin several weeks after urethritis or diarrheal illness.
* **asymmetric distribution btw ankles, knees, and feet**.
* **chronic disease involves spine**.
* extraarticular manifestations = **conjunctivitis, cardiac conduction abnormalities, aortic regurg**.
* some have **recurrent arthritis, tendinitis, and fasciitis** with significant impairment.
69
**Enteritis-Associated Arthritis**
* from GI infections with **Yersinia, Salmonella, Shigella, or Campylobacter**.
* **arthritis appears suddenly in knees and ankles**.
* **remits** after 1 yr.
70
**Psoriatic Arthritis**
* in **10% ppl with psoriasis**.
* **affects small hand and foot joints** but can involve knees, ankles, hips, and wrists.
* **spinal disease in 20-40%**.
* less joint destruction than RA.
71
**Bacterial Arthritis**
* by **gonococcus, staph, strep, H influenzae (kids \<2yrs), gram (-) rods**.
* Salmonella in sickle cell pts.
* **single joint affected**, usually **knee**.
* _predisposing conditions_: immune deficiency, debilitating illness, joint trauma, chronic arthritis, and IV drug use.
72
**Tuberculous Arthritis**
* **insidious** **chronic arthritis** from **hematogenous spread or nearby TB osteomyelitis**.
* involves **hips, knees, and ankles**.
* **chronic disease** ⇒ severe destruction with **fibrous ankylosi**s.
73
**Lyme Arthritis**
* in **60-80% untreated** ppl after **weeks to 2 yrs** after initial **infection by B. burgdorferi**.
* **oligoarticular, remitting, and migratory arthritis of large joints** (knees, shoulders, elbows, ankles).
* **clears spontaneously or with antibiotics**.
* 10% ⇒ permanent deformities.
74
**Viral Arthritis**
* may be **from direct infection or from autoimmune response to viral infection**.
* HIV-related seems to be autoimmune
75
**Gout**
* **transient attacks of acute arthritis from crystallization of urates around joints** ⇒ chronic gouty arthritis and tophi (large aggregates of urate crystals and inflammation).
* caused by hyperuricemia (\>6.8). Only **0.5% of hyperuricemics get gout.**
* _pathogenesis_: **hyperuricemia** from overproduction or reduced renal excretion (lack uricase).
* ↑ risk with **obesity and alcohol. **
* **thiazides** ⇒ ↓ urate excretion.
* also caused by lead toxicity.
* **_overproduction_**: 10% of cases. from **↑ nucleic acid turnover** (cancer, psoriasis, tumor lysis). **HGPRT deficiency** (lack = **Lesch-Nylan Syndrome**).
* **_↓ renal excretion_**: 90% cases. **↓ filtration and underexcretion of uric acid**. ** URAT1** imporant for reabsorption.
* **deposition of MSU** (monosodium urate) **affected by temp** and intra-articular **concentrations of urates and cations**. phagocytosed by macrophages ⇒ release **IL-1beta ⇒ recruit and activate neutrophils ⇒ acute arthritis**.
* **recurrent rounds ⇒ chronic arthritis and tophus formation**, cartilage damage, joint compromise.
* _morphology_: **_acute arthritis_** = dense **neutrophilic infiltrate in synovium and synovial fluid. slender, birefringent MSU crystals** in edematous and congested **synovium and in neutrophils**. scattered chronic inflammation.
* **_chronic tophaceous arthritis_** = urates encrust articular surface ⇒ **synovial deposits. synovium hyperplastic and fibrotic**, ↑ inflammatory infiltrates. ** pannus extends to juxta-articular bone ⇒ erosions, fibrosis, bony ankylosis**.
* **_tophi_** = pathologic lesions. **masses of urates, crystalline or amorphous with intense mononuclear inflammation and foreign body giant cells**. occur on **ear, olecranon, patellar bursae, periarticular ligaments and CT**.
* **_gouty nephropathy_** = renal medullary MSU deposition and uric acid stones. obstruction ⇒ 2° pyelonephritis.
* _presentation_: yrs of asymptomatic hyperuricemia followed by **excruciating joint pain with hyperemia and warmth**. usually **monoarticular** and on **big toe**, then involves **insteps, ankles, or heels/knees**.
* resolves ⇒ **asymptomatic intercritical period**. usually recur with ↑ frequency and **become polyarticular with joint effacement.**
* see with **atherosclerosis and HTN**. 20% get gouty nephropathy
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**Calcium Pyrophosphate Crystal Deposition Disease (Pseudo-Gout)**
* aka chondrocalcinosis
* **age \>50yrs; 30=60% \>85yrs**
* autosomal dominant = **mutated ANKH** encoding pyrophosphate transport channel.
* **_2° form_** associated with **trauma, hyperparathyroidism, hemachromatosis, and diabetes.**
* altered matrix synthesis and pyrophosphate degradation
* **similar to gout**: crystals formed in cartilage, seed the joint where macrophages engulf them, activate inflammasomes ⇒ IL-1beta.
* neutrophil recruitment and recurrence ⇒ joint damage.
* affects **knees, wrists, elbows, shoulders, and ankles**.
* _morphology_: crystals = **chalky, white, friable deposits**. rarely make tophus. **oval blue-purple aggregates**, weakly birefringent, geometric shapes.
* chronic lesions have **mononuclear cell infiltrates and fibrosis**.
77
**Ganglion Cysts**
* **small, multiloculated cystic lesions of CT** near **joint capsules or tendon sheaths** (wrist).
* from **myxoid degeneration and softening of CT**.
* NOT lined by epithelium. DO NOT communicate with joint space.
78
**Synovial Cysts**
* **herniations of synovium through joint capsule**.
* synovial lining can be **hyperplastic with scattered inflammation**.
* **Baker's cyst** = in popliteal fossa.
79
**Tenosynovial Giant-Cell Tumor**
* **benign neoplasms involving synovial membranes, tendon sheaths, and bursae**.
* **t(1;2) chromosomal translocation** fuses CSF1 to promoter for alpha3 chain of collagen type IV ⇒ **overexpress CSF1 **⇒ accumulation of **swarms of macrophages.**
* **_diffuse type_** = pigmented villonodular tenosynovitis
* present with **knee pain (80%), locking and swelling, ↓ ROM**, aggressive ⇒ **bone and soft tissue erosion**.
* **_localized type_** = **giant cell tumor of tendon sheath.**
* **solitary painless mass in tendon sheaths of wrist and fingers**. 15% have cortical bone erosion.
* _morphology_: **red-brown to mottled orange lesions**.
* **_diffuse_** = synovium is **tangled mat of red-brown folds**, nodules, and finger projections **along articular surface into subsynovial tissu**e.
* **_localized_** = **well-circumscribed nodular** tumors that may be attached to synovium by **pedicle**.
* neoplastic cells are **polyhedral** and look like synoviocytes. many **macrophages** with **hemosiderin, multinucleated giant cells**.
80
**Lipoma**
* **most common benign soft tissue tumor** in adults.
* **soft, mobile, and painless** (except angiolipomas).
* _morphology_: **well-encapsulated tumor** of mature adipocyte.
* rarely large, intramuscular, poorly circumscribed.
* _tx_: **excision** = cure
81
**Liposarcoma**
* common adult sarcoma.
* appear **age 40-70yrs**.
* **large masses in deep soft tissues of proximal extremities and retroperitoneum**.
* three types:
* **_well-differentiated_** = indolent.
* **_pleomorphic_** = very **aggressive**.
* **_myxoid/round cell_** = intermediate
* **t(12;16)** translocation. ** CHOP/TLS fusion gene**.
* _morphology_: cells show **fatty differentiation. **
* lipoblasts mimic fetal fat cells with **clear cytoplasmic lipid droplets scalloping the nucleus**.
82
**Nodular Fasciitis**
* aka pseudosarcomatous fasciitis
* _morphology_: **large, nodular,** with **ill-defined margins.**
* lesions **cellular and highly mitotic** with plump, reactive, **immature-appearing fibroblasts or myofibroblasts** arranged randomly or in **intersecting fascicles.**
* **myxoid stroma and scattered lymphocytes**.
* _presentation_: several week history of **solitary, rapidly growing, maybe painful mass on volar forearm, chest, or back**.
* rarely recur after excision.
83
**Myositis Ossificans**
* reactive **fibroblastic proliferation with metaplastic bone.**
* _morphology_: initially looks like nodular fasciitis, then zone of osteoblasts ⇒ deposits of ill-defined trabeculae of woven bone ⇒ **well-formed cancellous bone**. after ossification, **intratrabecular areas have marrow.**
* _presentation_: after **trauma in adolescents and young adults.**
* initially painful ⇒ **painless, hard, well-demarcated mass**
* _tx_: excision
84
**Palmar Fibromatosis**
* aka **Dupuytren contracture**.
* superficial fibromatosis = benign fibroproliferative lesion with abundant dense collagen.
* M\>F.
* **irregular thickening of palmar fascia**, bilateral in 50%.
* attachment to overlying skin ⇒ skin puckering ⇒ **slowly progressive flexion contracture of 4th and 5th fingers**.
* _morphology_: 1-15cm g**ray-white, rubbery, poorly demarcated mass** made of **banal fibroblasts** in **broad sweeping fascicles** infiltrating neighboring tissues.
85
**Deep-Seated Fibromatosis**
* **locally aggressive, recurrent** neoplasm with little potential for metastasis.
* **mutations = APC or beta-catenin**
* 3 types: extra-abdominal, abdominal, intra-abdominal.
* **_extra-abdominal_**: **M=W**; in musculature of **shoulder, chest wall, back, and thigh**.
* **_abdominal_**: in **anterior abdominal wall** in women **during or after pregnancy**.
* **_intra-abdominal_**: in **mesentary or pelvic walls**.
* particularly in **Gardner syndrome**.
* _morphology_: 1-15cm **gray-white, rubbery, poorly demarcated lesion** made of **banal fibroblasts in broad sweeping fasciles** that infiltrate neighboring tissues.
* _tx_: surgery, tamoxifen, chemo, radiation.
86
**Fibrosarcoma**
* in **deep soft tissue**, usually in **extremities**.
* \>50% recur, 25% metastasize.
* _morphology_: **unencapsulated, infiltrative, soft (fish-flesh consistency)** masses with **focal hemorrhage and necrosis**.
* **all degrees of differention**: cellular fibromatosis to highly cellular anaplastic appearance.
87
**Malignant Fibrous Histiocytoma**
* **fibrosarcoma variant** with extensive pleomorphism and storiform architecture.
88
**Rhabdomyosarcoma**
* **most common soft tissue sarcoma of kids.**
* in **head and neck or GU tract**.
* **aggressive** neoplasms.
* three types: embryonal, alveolar, pleomorphic.
* **_embryonal_**: (60%) **most common**. **kids \<10yrs**. ** nasal cavity, orbit, middle ear, prostate, and paratesticular** region.
* parental isodisomy of **11p15 ⇒ overexpression of IGFII.**
* **botryoidessubtype** in walls of hollow, mucosa-lined structures = better prognosis
* **_alveolar_**: (20%) **middle adolescence in deep musculature of extremities.**
* **t[2,13]** fuses PAX3 to FOXO1a and **t[1,13]** fuses PAX7 to FOXO1a
* **_Pleomorphic_**: rare. In **deep soft tissue of adults**.
* _morphology_: **rhabdomyoblast round or elongated** with **sarcomeres** and **myogenic markers**.
* **_embryonal_**: **soft, gray, infiltrative** masses. **sheets of round and spindled cells in myxoid stroma**.
* **botryoid** subtype looks like **cluster of grapes**.
* **_alveolar_**: **network of fibrous septae **⇒ clusters that look like alveoli. **mod sized tumor cells, little cytoplasm**.
* **_pleomorphic_**: resemble pleomorphic sarcomas.
* _tx_: surgery, radiation, chemo.
89
**Leiomyomas**
* **benign smooth muscle tumors** typically in **uterus**
* mass\<1-2cm, made of **fascicles of bland appearing smooth muscle cells, few mitoses.**
* **autosomal dominant disorder **when: **multiple cutaneous leiomyomas** from **arrector pili muscles**, with **uterine leiomyomas,** and **renal cell carcinomas**.
* loss of function of **fumarate hydratase gene.**
90
**Leiomyosarcomas**
* 10-20% of soft tissue sarcomas.
* **F\>M.**
* in **skin and deep soft tissues of extremities and retroperitoneum**.
* **_superficial_** = small and **good prognosis**.
* **_retroperitoneal_** = larger, **non-resectable ⇒ death** by local extension and metastasis.
* _morphology_: **painless, firm mass**.
* **malignant spindle cells in interweaving fascicles; bundles of muscle filaments** ultrastructurally and on immunohistochemistry.
91
**Synovial Sarcoma**
* unknown origin.
* btw age **20-50yrs**.
* in **deep soft tissues of lower extremity (knee and thigh)**.
* **t[x;18]** ⇒ chimeric transcription factor
* _morphology_: **_biphasic_ = cuboidal epithelial and spindled mesenchymal differentiation**.
* **_monophasic_ = mesenchymal**.
* may have **calcified concretions**.
* tx: surgery, chemo.
* good 5yr survival, poor 10yr survival.
92
**Plantar Fibromatosis**
* superficial fibromatosis = benign fibroproliferative lesion with abundant dense collagen.
* M\>F.
* **irregular thickening of plantar fascia of foot**.
* rare to be bilateral or have contractures.
* _morphology_: 1-15cm g**ray-white, rubbery poorly demarcated mass** made of **banal fibroblasts in broad sweeping fascicles** that infiltrate neighboring tissues.
93
**Penile Fibromatosis**
* aka **Peyronie disease**.
* superficial fibromatosis = benign fibropriliferative lesion with abundant dense collagen.
* M.
* on **dorsolateral penis ⇒ abnormal curvature and/or urethral obstruction**.
* _morphology_: 1-15cm **gray-white, rubbery, poorly demarcated lesion** made of **banal fibroblasts in broad sweeping fascicles** that infiltrate neighboring tissues.
94
**Benign Fibrous Histiocytoma**
* aka **Dermatofibroma**
* common **painless, slow growing lesion of dermis and subcutis**.
