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Diseases of the Immune System (Autoimmune Diseases (Systemic Lupus…

- - - - often depending on route
        
        local reaction: Ag confined (skin (contact-->urticaria), GI (ingestion-->diarrhea), or lung (inhalation-->bronchoconstriction)); ex: common forms of skin and food allergies, hay fever, and certain forms of asthma; Susceptibility has a strong
        genetic component, and the term atopy is used to imply familial predisposition to such localized reactions. (ex nasobronchial allergy (hay fever, some forms of asthma,..) often have family history) implicated genes: HLA, cytokines (may control TH
        2 responses), a component of the FcεRI, and ADAM33, a metalloproteinase that may be involved in tissue remodeling in the airways
        
        systemic disorder: Systemic exposure to pr Ags (ex bee venom) or drugs (ex penicillin)--> systemic anaphylaxis: Within mins--> itching, urticaria (hives), and skin erythema--> profound respiratory difficulty (pulmonary bronchoconstriction + hypersecretion of mucus; Laryngeal edema-->upper airway obstruction), musculature of GI affected-->vomiting, abdominal cramps,diarrhea; may be systemic vasodilation w/ a fall in blood P (anaphylactic shock)--> circulatory collapse + death within mins
  - - - Ab classes: complement-fixing (i.e., IgG and IgM) + bindong phagocyte Fc Rs (IgG); During active phase: consumption of complement--> decr serum complement levels.
      - MORPHOLOGY: necrotizing vasculitis (fibrinoid necrosis), microthrombi, and superimposed ischemic necrosis accompanied by acute inflammation of the affected organs; lesions tend to resolve, esp when they were brought about by a single exposure to Ag
  - - - in the process of eradicating the infection, host tissues are injured. (viral hepatitis)
      - Rarely, Abs/T cells cross-react with a host tissue (rheumatic heart disease)
      - T cell responses against persistent microbes (tuberculosis)
      - immune complexes deposit in tissues + trigger inflammation; (poststreptococcal glomerulonephritis)
  - - - DCs--> IL-12/(IL-1, IL-6, or IL-23) --> naive T cells differentiate into TH1/TH17
        (IFN-γ (by NK + TH1 cells themselves)--> further promotes TH1 differentiation)
        -several systemic diseases (DM-I, MS) caused by TH1 +TH17 reactions against self Ags, and Crohn disease may be caused by uncontrolled reactions involving the same T cells but directed against intestinal bacteria
      - Delayed-Type Hypersensitivity: a T cell–mediated reaction that develops in response to Ag challenge in a previously sensitized individual; is delayed for 12-48 hrs; classic example: tuberculin reaction--> 8-12 hrs after intracutaneous injection of tuberculin--> local area of erythema + induration, reaching a peak (1-2 cm in d) in 24-72 hrs and thereafter slowly subsides;
        DTH reactions are mediated primarily by TH1 cells; immunosuppression,etc--> negative tuberculin response even in the presence of a severe infection.
- - - - monoclonal gammopathy (abnorm amounts of specific Ig)-->M (myeloma) protein spike on serum electrophoresis
      - plasma cells also may synthesize and secrete either λ or κ light chain (Bence Jones prs); present in serum/urine/both in all patients; presence necessary but not sufficient to produce amyloidosis
    - - Chronic skin infections caused by “skin-popping” of narcotics
      - in association w/ tumors not derived from immune cells (2 most common: renal cell carcinoma + Hodgkin lymphoma)
      - most common cause
        
        before: tuberculosis, bronchiectasis, and chronic osteomyelitis (but now w/ antimicrobial therapies...)
        
        chronic inflammation caused by AI states (ex seen in 3% of RA cases)
  - - - most common
        
        Aβ amyloid: core of cerebral plaques + amyloid deposits in cerebral blood vessels in Alzheimer; derived from a much larger transmembrane GP called amyloid precursor protein (APP)
        
        AA (amyloid-associated) fibril
        
        AL (amyloid light chain)
      - β2 -Microglobulin
      - Transthyretin (TTR)
      - Amyloid deposits derived from diverse precursors such as hormones (procalcitonin) and keratin
  - - - secondary: kidneys, liver, spleen, lymph nodes, adrenals, and thyroid,...
      - primary amyloidosis more often: heart, GI tract, respiratory tract, peripheral nerves, skin, and tongue.
    - - small amounts: surface of the cut organ + iodine and sulfuric acid--> brown staining of amyloid deposits.
      - larger amounts: organ frequently enlarged + tissue: gray w/ a waxy, firm consistency
    - - Kidney: most common + serious; Gross: unchanged/abnormally large; in long-standing cases, may be reduced in size.
      - Spleen
        
        sago spleen: deposits limited to splenic follicles (granules)
        
        lardaceous spleen: splenic sinuses + extending to splenic pulp, with formation of large, sheetlike deposits
      - Liver: normal function may be preserved even in setting of severe involvement.
      - Heart: most characteristic gross findings: gray-pink, dewdrop-like subendocardial elevations, partic evident in A chambers
        
        isolated organ involvement: senile amyloidosis
        
        as part of a systemic distribution: usually of the AL form.
    - - endocrine glands: adrenals, thyroid, and pituitary; large amounts may be present w/o disturbance of function.
      - GI tract: amyloid may be found at all levels, sometimes tumorous masses (ex: nodular depositions in tongue-->macroglossia); bc of frequency in systemic cases, gingival, intestinal, and rectal biopsies serve in the diagnosis
  - - - Renal: severe proteinuria (nephrotic syndrome) often major cause of symptoms in reactive systemic amyloidosis. Progression--> renal failure (important cause of death)
      - hepatosplenomegaly: rarely causes significant clinical dysfunction
      - Cardiac: conduction disturbances/restrictive cardiomyopathy
    - - Biopsy + Congo red: most important tool; biopsy taken from organ suspected to be involved (renal biopsy in urinary abnormalities; Rectal + gingival in generalized amyloidosis; abdominal fat aspirates (simple low risk)
      - suspected cases of AL amyloidosis: serum + urinary pr electrophoresis + immunoelectrophoresis; Bone marrow shows plasmacytosis
      - Proteomic analysis: detection of small amounts (from fat aspirates) + definitive identification of type of amyloid.
    - - generalized amyloidosis; poor (survival time after diagnosis: 1-3 yrs)
        
        AA amyloidosis: prognosis depends to some extent on the control of underlying condition
        
        Patients w/ myeloma-associated amyloidosis: poorer prognosis
      - Resorption after treatment of associated condition: rare
- - - - Hyperacute Rejection
        
        in a presensitized host: 1. multiparous women 2.individuals exposed to foreign HLA (on platelets/leukocytes) from previous blood transfusions. 3. previously rejected an organ transplant
        
        within min-few hrs; typically recognized by surgeon just after vascular anastomosis completed
        
        nonrejecting kidney graft: regains a normal pink color + tissue turgor + promptly excretes urine,
        this kidney rapidly becomes cyanotic, mottled, and flaccid and may excrete only a few drops of bloody fluid
        
        screening recepients for pre-formed anti-HLA Abs + cross-matching (testing recipients for presence of Abs directed against the donor’s lymphocytes)--> hyperacute rejection occurs in <0.4% of transplants.
      - Acute Rejection: within ds-ws in a nonimmunosuppressed host / mths/yrs in adequate immunosuppression; caused by both mechanisms + one or the other may predominate, or both may be present
        
        Acute cellular rejection: within first mths + typically accompanied by clinical signs of renal failure; Cyclosporine (immunosuppressive) is nephrotoxic + induces arteriolar hyaline deposits. biopsy is used to distinguish rejection from drug toxicity; patients typically respond promptly to incr immunosuppressive therapy.
        
        Acute humoral rejection: (rejection vasculitis); the proliferative vascular lesions mimic arteriosclerotic thickening + caused by cytokines (stimulate prolif of vascular smooth muscle cells) Local deposition of complement breakdown products (specifically C4d) used to detect Ab-mediated rejection of kidney allografts.
      - Chronic Rejection: mths-yrs w/ progressive rise in serum creatinine levels over a period of 4-6 mths; vascular lesion may be caused by cytokines released by activated T cells that act on the cells of the vascular wall, and it may be the end stage of the proliferative arteritis described earlier
  - - - GVHD
        
        happens most commonly in setting of allogeneic HSC transplantation (usually minor HC mismatches), it also may occur after transplantation of solid organs rich in lymphoid cells (e.g., the liver) or after transfusion of nonirradiated blood.
        
        when immunologically competent T cells (both CD4 and 8 or their precursors) transplanted into recipients who are immunologically compromised
        
        types
        
        Acute: (d-ws after)--> epithelial cell necrosis in: liver (jaundice), skin (generalized rash), and gut (bloody diarrhea)
        
        Chronic: may follow acute syndrome or occur insidiously; develop lesions resembling those of SS + manifestations mimicking other AI disorders
        
        solutions
        
        can be minimized but not eliminated by HLA matching
        
        donor T cells can be depleted before marrow transplant--> risk of GVHD is reduced, but incidence of graft failure + recurrence of leukemia incr. (multifunctional T cells not only mediate GVHD but also are required for the efficient engraftment of the transplanted HSCs and elimination of leukemia cells (so-called graftversus-leukemia effect)
      - Immune Deficiencies: often of prolonged duration in recipients of HSC transplants. reasons: slow reconstitution of recipient’s adaptive immune system; susceptible to a variety of infections, mostly viral
- - - - DCs (sometimes called interdigitating DCs)
        
        location: in + under epithelia (ex: Langerhans cell of epidermis); also present in T cell zones of lymphoid tissues + in interstitium of many nonlymphoid organs (ex heart and lungs)
        
        function: express high levels of MHC-II + T cell costimulatory molecules + function to capture and present Ags to T cells
        
        One subset: plasmacytoid DCs (resemblance to plasma cells) present in blood + lymphoid organs; major sources of antiviral interferon-1
      - FollicularDCs
        
        location: in germinal centers of lymphoid follicles in spleen + lymph nodes
        
        function: bear Rs for Fc tails of IgG + complement prs--> trap Ags bound to Abs + complement--> display Ags to activated B cells in lymphoid follicles + promote secondary Ab responses, but not involved in capturing Ags for display to T cells
    - - B cells present peptides to helper T cells-->receive signals stimulating Ab responses to pr Ags
      - MQs ingest + display peptides to T lymphocytes--> T cells *MQs to kill the microbes, the central reaction of cell-mediated immunity.
  - - - 60-70% of lymphocytes in peripheral blood and are the major lymphocyte population in splenic periarteriolar sheaths and lymph node interfollicular zones
      - 95% recognize only peptide fragments bound to MHC; T cells recognize only peptides displayed by that person’s MHC, which, of course, are the only MHC molecules that the T cells normally encounter= MHC restriction; normal function of MHC molecules is to display peptides for recognition by T lymphocytes.
      - co R: CD4 expressed on 50-60% of mature T cells; CD8 expressed on 40%; CD28:: R for molecules induced on APCs by microbes (and are called costimulators),
    - - each person: unique MHC Ag profile on their cells; The combination of HLA alleles for each person= HLA haplotype
      - ability of any given MHC to bind peptide Ags generated from a particular pathogen: determine whether a specific person’s T cells can actually “see” and respond to that pathogen
      - many AI diseases associated w/ particular HLA alleles
      - hetero can express 6 different HLA-I s+ as many as 20 different MHC-II--> different MHCs bind to different peptide fragments--> present a wide array of peptide Ags
    - - recognize and respond to many more chemical structures
      - Ab diversity generated during somatic rearrangements of Ig genes; 5 classes/isotypes: IgG, IgM, and IgA constitute >95% of circulating Abs. (IgE present in circulation at very low [ ] + also found attached to surfaces of tissue mast cells; and IgD expressed on the surfaces of B cells but not secreted)
      - 10-20% of circulating peripheral lymphocyte population
    - - origin: the common lymphoid progenitor that gives rise to T and B cells
      - R
        
        inhibitory: recognize self MHC-I; normally dominate over activating
        
        activating: recognize molecules expressed/upregulated on stressed/infected/DNA damage cells (in which MHC-I downreg)
- - - - regulate lymphocyte responses and effector functions in adaptive immunity: prolif + diff of lymphocytes (e.g., IL-2, IL-4), *various effector cells; major sources: CD4+ helper T cells
      - stimulate hematopoiesis: many are CSFs
      - involved in innate immunity and inflammation: major cytokines in this group: TNF + IL-1 + chemokines. also: IL-12, IFN-γ, IL-6, IL-23... Major sources: *MQs + DCs, endothelial cells, lymphocytes, mast cells,...
    - - CD4+ Th cells--> IL-2 secretion + expression of high-affinity Rs for IL-2--> stimulates their proliferation; Some of the progeny of the expanded pool of T cells differentiate into effector cells (Th1, 2, 17,..)
      - Some CD4+ T cells remain in lymphoid organs in which they were * --> then migrate into follicles + stimulate Ab responses; called follicular helper T cells
      - Activated CD8+ lymphocytes differentiate into CTLs,
- - - - immune complex deposition: most organ damage; *classical complement pathway (type III hypersensitivity); 75% of patients will have reduced serum levels of C3 + C4 at the time of SLE flares
      - diff autoAbs-->diff manifestations (type II hypersensitivity)
        
        blood cells--> opsonization-->phago-->cytopenias
        
        PLs-->incr thrombosis (AntiPL syndrome); Paradoxically interfere w/ clotting tests + called “lupus anticoagulants.”; AutoAbs also produced against clotting factors (thrombin)
        
        CNS Rs for NTs: neuropsychiatric complications
      - nuclei of damaged cells (bc ANAs can't permeate intact cells) react w/ ANAs, lose their chromatin pattern + become homogeneous--> LE/hematoxylin bodies; LE cell test + in as many as 70% of patients but now largely of historical interest.
    - - Blood Vessels: acute necrotizing vasculitis in small arteries and arterioles;
      - kidneys: renal failure most common cause of death; (intersitial + tubular lesions also) + glomerular
        
        Minimal mesangial lupus nephritis (class I): not detectable by light microscopy; rarely encountered
        
        Mesangial proliferative lupus nephritis (class II): in 10-25% of cases; associated w/ mild clinical symptoms
        
        Focal lupus nephritis (class III): in 20-35%; clinical presentation: mild microscopic hematuria + proteinuria to a more active urinary sediment with RBC casts and acute, severe renal insufficiency.
        
        Diffuse lupus nephritis (class IV): most serious form; most common (in 35-60%); distinguished from class III (in fewer than half) by involvement of half or more of glomeruli; Most have hematuria w/ moderate to severe proteinuria, hypertension, and renal insufficiency.
        
        Membranous lupus nephritis (class V): in 10-15%; is the designation for glomerular disease characterized by widespread thickening of the capillary wall (incr deposition of basement membrane–like material, as well as accumulation of immune complexes); severe proteinuria with overt nephrotic syndrome
        
        Advanced sclerosing lupus nephritis (class VI): complete sclerosis of >90% of glomeruli; clinical end stage renal disease.
      - Skin: “butterfly pattern” in half of the cases; photosensitivity;
      - Joints: swelling + nonspecific mononuclear cell infiltration in synovial membr. (Erosion of the membr + destruction of articular cartilage, such as in RA, are exceedingly rare)
      - CNS: very common; vascular lesions(Small vessel angiopathy w/ noninflam intimal proliferation is most frequent; vasculitis uncommon) -->ischemia / multifocal cerebral microinfarcts
      - Other Organs
        
        spleen: Central penicilliary arteries thickening + perivascular fibrosis-->onion-skin lesions
        
        serosal membranes (partic Pericardium and pleura)
        
        Involvement of the heart: primarily in the
        form of pericarditis; Libman-Sacks endocarditis (nonbacterial verrucous endocarditis: warty deposits on leaflets) less common; coronary artery disease (immune deposits + alterations in lipid metabolism bc of glucocorticoid treatments + hypertension bc of renal disease)
        
        lungs: interstitial fibrosis
        
        liver: nonspecific inflammation of the portal tracts.
    - - typical patient: young woman w/ rarely all the following: a butterfly rash, fever, pain and swelling in one or more peripheral joints, pleuritic chest pain, and photosensitivity.
      - Recent strategies: B cell depletion w/ antiCD20 Ab (Rituximab) + by blocking GFs
      - w/ appropriate therapy-->flareups + remissions spanning a period of yrs or even decades. During acute flareups, incr deposition of immune complexes and the accompanying complement*--> hypocomplementemia;
      - w/o therapy some patients have benign course w/ only skin manifestations + mild hematuria for yrs; 5-yr survival in 95% of patients
      - most common causes of death: renal failure, intercurrent infections, and CV disease; incidence of cancer also incr (particularly B cell lymphomas)
    - - Antinuclear Abs (ANAs): found in 100% of patients; are not specific
        
        categories
        
        DNA
        
        histones
        
        nonhistone prs bound to RNA
        
        nucleolar Ags
        
        detection
        
        most widely used: indirect immunofluorescence assay (IFA): extremely sensitive (95%) but specificity is quite limited (other AI, chronic infections, and cancer test + as well); ANAs seen in 5-15% of healthy ppl w/ incidence incr w/ age; 4 staining patterns: homogeneous or diffuse, rim or peripheral, speckled, and nucleolar (each can be suggestive of the presence of specific autoAbs)
        
        multiplex flow cytometry immunoassays: can simultaneously test for multiple specific autoAbs, but may lack sensitivity of IFA
        
        Anti-dsDNA + Smith (Sm) Ag can be detected by ELISA or multiplex flow methods and are specific for SLE.
      - Other autoAbs: against blood cells in many; AntiPL Abs present in 40-50% of patients (some bind to cardiolipin--> false + for syphilis)
    - - Environmental Factors
        
        Cigarette smoking: may modulate the production of autoAbs
        
        Sex hormones: 10x more common in women during reproductive years than in men of similar ages but only 2-3x more common in women during childhood or after 65; However, treatment w/ oral contraceptives didn't influence the frequency or severity of disease flares--> factors other than hormones may account
        
        UV radiation: (sun exposure) exacerbates lesions of SLE; mechanism: UV radiation-->apoptosis of host cells--> incr burden of nuclear fragments + inflammatory responses to the products of dead cells.
        
        Drugs: procainamide + hydralazine--> demethylation of DNA--> influence expression of genes involved in the development of AI / ability of DNA to activate host cells--> induce an SLE-like disease, although typically glomerulonephritis does not develop.
      - Immunologic Abnormalities in SLE
        
        TLR signals: TLRs that recognize DNA (TLR9) + RNA (TLR7) produce signals that activate B cells specific for self nuclear Ags.
        
        Failure of B cell tolerance: defects in both central and peripheral tolerance--> higher frequency of autoreactive B cells than that typical for healthy people.
        
        Type I interferons: IFN-alpha: exposure + production in blood cells
      - Genetic Factors
        
        HLA association odds ratio
        
        HLA-DR2 / HLA-DR3: 2 to 3
        
        HLA-DR2 + HLA-DR3: 5
        
        Other genes
        
        Genetic deficiencies of classical pathway complement prs, esp C1q, C2, or C4, are seen in about 10% of patients--> defective clearance of immune complexes and apoptotic cells + failure of B cell tolerance
        
        A polymorphism in the inhibitory Fc R, FcγRIIb, in some patients; may contribute to inadequate control of B cell activation
        
        Familial association: up to 20% of clinically unaffected first-degree relatives may have autoaAbs; concordance in monozygotic twins (25%) vs dizygotic twins (1-3%).
  - - - Role of Infections and Tissue Injury
        
        molecular mimicry: may share cross-reacting epitopes with self Ags; ex: rheumatic heart disease + streptococci
        
        resultant tissue necrosis + inflam--> upregulation of costimulatory molecules on APCs--> breakdown of T cell anergy + subsequent T cell activation
        
        infections may paradoxically protect affected persons from some AI, notably DM-1 + MS
      - UV radiation-->cell death-->exposure of nuclear Ags
      - smoking a risk factor for RA bc it leads to chemical modification of self Ags
      - local tissue injury-->release of self Ags + AI responses; The activation of such autoreactive T cells is called “epitope spreading,” because the immune response “spreads” to epitopes that were not recognized initially--> chronicity in some AI
    - - susceptibility genes
        
        tendency to run in families
        
        Several are linked w/ HLA locus, esp class II alleles (HLA-DR, -DQ); most ppl w/ a susceptibility-related MHC never develop any disease, and, conversely, ppl w/o can develop the disease
        
        many genetic polymorphisms are associated w/ different AI diseases; Some seem to be associated w/ several diseases; others disease specific
      - gender bias : many more common in women than in men; maybe bc of hormone effects...
  - - - B cell: “slippage” (like in T cell system)--> B cells bearing Rs for a variety of self Ags (thyroglobulin, coll, and DNA) can be found in healthy persons.
        
        apoptosis
        
        2nd rearrangement of Ag R genes: receptor editing
      - T cell: putative TFs--> expression of peripheral tissue Ags in thymus (making it an immunologic mirror of self). ex: autoimmune regulator (AIRE); mutations--> an AI polyendocrine syndrome
        
        Ag-induced deletion (death) (negative selection)
        
        differentiate into regulatory T cells
    - - Anergy
        
        T: If 2nd costimulatory signals not delivered/ an inhibitory R (rather than costimulatory) engaged--> anergic cell; bc costimulatory are not strongly expressed on most normal tissues, encounter between autoreactive T cells + self Ags may result in anergy
        
        B cells can also become anergic if they encounter Ag in the absence of specific helper T cells
      - Suppression by regulatory T cells
        
        mechanism
        
        competitive blocking of B7 molecules on APCs
        
        secretion of immunosuppressive cytokines (ex IL-10, TGF-β)
        
        reg cells express
        
        CD25, one of the chains of the R for IL-2 + require IL-2 for their generation and survival.
        
        FoxP3: necessary for the development of regulatory cells; mutations responsible for IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome),
      - Activation-induced cell death
        
        death R Fas engaged by its ligand coexpressed on same/neighboring cells; same pathway important for deletion of self-reactive B cells by Fas ligand expressed on T cells.: mutation: AI lymphoproliferative syndrome (ALPS), characterized by lymphadenopathy + multiple autoAb including anti-DNA
        
        MitC pathway may also be involved
  - - - also systemic B cell hyperactivity
      - patients w/ high-titer anti-SS-A Abs more likely to have systemic (extraglandular) manifestations
      - Genetic variables: nheritance of certain class II MHC alleles predispose the development of specific RNP autoAbs
      - caused by CD4+ reactions against unknown Ags in ductal epith cells of exocrine glands.
    - - nose: even perforation of the nasal septum
      - respiratory passages: secondary laryngitis, bronchitis, pneumonitis
      - 25% of patients (esp those w/ anti-SS-A Abs) acquire extraglandular disease involving CNS, skin, kidneys, and muscles (synovitis, pulmonary fibrosis, and peripheral neuropathy)
      - Renal lesions: mild interstitial nephritis w/ tubular transport defects (unlike in SLE, glomerulonephritis is rare)
      - primary targets
        
        Lacrimal glands: destruction-->lack of tears-->keratoconjunctivitis sicca (dry eyes)
        
        salivary glands--> xerostomia (dry mouth); enlarged as a result of lymphocytic infiltrates
    - - 90% of cases: women between the ages of 35-45 yrs
      - 40x incr risk for developing a non-Hodgkin B cell lymphoma
    - - an isolated disorder (primary form) (sicca syndrome)
      - more often (60%): w/ another AI disease (secondary form). (RA: most common, SLE, polymyositis, systemic sclerosis, vasculitis, or thyroiditis)
  - - - Musculoskeletal System: Synovial hyperplasia + inflammation in early stages-->fibrosis (diff w/ RA: joint destruction not common) ; In 10%: inflammatory myositis indistinguishable from polymyositis may develop
      - Lungs (in >50%): pulmonary hypertension (Pulmonary vasospasm) +/ interstitial fibrosis
      - GI tract: in 90%
        
        Progressive atrophy + coll fibrous replacement of the muscularis: any level of but most severe in esophagus (lower 2/3 inflexibile; mucosa is thinned + ulcerated + excessive collagenization of the lamina propria + submucosa
        
        GE reflux and its complications (Barrett metaplasia); Loss of villi + microvilli--> malabsorption syndrome
      - Kidneys (in 2/3): thickening of vessel walls of interlobular arteries (restricted to vessels 150-500 µm in d + not always associated w/ hypertension (in 30% + in 20% of those patients: malignant hypertension-->vascular alterations more pronounced + often fibrinoid necrosis w/ thrombosis + infarction--> often die of renal failure, accounting for 1/2 the deaths attributable to SS)); no specific glomerular changes.
      - Skin: Cutaneous involvement is the usual presenting manifestation + eventually appears in 95%
        
        Histologiic
        
        Capillaries + small arteries: thickening of basal lamina, endothelial cell damage, partial occlusion--> hyaline thickening of the walls
        
        perivascular infiltrates (CD4+ cells) + edema--> replaced by progressive fibrosis of dermis-->becomes tightly bound to subcutaneous; marked incr of compact collagen in dermis w/ thinning of epidermis, atrophy of dermal appendages
        
        Focal + sometimes diffuse subcut calcifications may develop, esp in patients w/ CREST syndrome
        
        gross: advanced stages: fingers clawlike; face becomes a drawn mask; Loss of blood supply may lead to autoamputation in terminal phalanges; atrophy of hands, w/ incr stiffness + eventually complete immobilization of joints
        
        vast majority of patients have diffuse, sclerotic atrophy of the skin, usually beginning in fingers and distal regions of upper extremities and extending proximally
      - Heart (1/3): Patchy myocardial fibrosis + thickening of intramyocardial arterioles; caused by microvascular injury + resultant ischemia (so-called cardiac Raynaud). bc of changes in the lung, R V hypertrophy + failure (cor pulmonale) are frequent
    - - Diffuse: initial widespread skin involvement, w/ rapid progression + early visceral involvement
      - Limited: relatively mild skin involvement, often confined to the fingers and face. Involvement of the viscera occurs late; also called CREST syndrome: frequent features of calcinosis, Raynaud phenomenon (reversible vasospasm: hands turn white on exposure to cold (vasospasm)--> blue (ischemia + cyanosis)--> red (reactive vasodilation), esophageal dysmotility, sclerodactyly, and telangiectasia
    - - women to men 3:1 w/ peak incidence in 50-60 yrs
      - distinctive feature of SS: striking cutaneous involvement; Almost all patients exhibit Raynaud phenomenon
      - In most: disease pursues a steady, slow, downhill course over many yrs, although in absence of renal involvement, life span may be normal; 10-yr survival rate: 35% to 70%; survival better w/ localized than the usual diffuse progressive disease;
- - - - Mechanisms of T Cell Depletion in HIV Infection
        
        qualitative defects in T cell function can be detected even in asymptomatic HIV infected ppl (reduced Ag-induced T cell proliferation, impaired TH1 cytokine production, and abnormal intracellular signaling; also selective loss of memory CD4+ T cells early in the course)
        
        Completion requires cell activation
      - Monocytes/Macrophages in HIV Infection
        
        bud relatively small amounts of virus from cell surface but contain large #s in IC vesicles
        
        quite resistant to the cytopathic effects of HIV
        
        infect and multiply in terminally differentiated nondividing MQs
        
        gatekeeper of HIV infection
        
        viral reservoirs and factories, whose output remains largely protected from host defenses.
        
        vehicle for HIV transport to various parts of the body, particularly the nervous system
        
        portal for initial transmission
        
        most infected ones found in tissues
      - Progression of HIV Infection
      - DCs in HIV Infection
        
        mucosal: capture the virus and transport it
        
        Follicular: important reservoirs; most virus particles found on the surface of their dendritic processes and retain the ability to infect
      - Life Cycle of HIV
      - B Cells and Other Lymphocytes in HIV Infection
        
        polyclonal B cell activation-->hypergammaglobulinemia + circulating immune complexes
        
        infection with CMV or EBV
        
        HIV gp41 itself can promote B cell growth and differentiation
        
        HIV-infected MQs produce incr amounts of IL-6--> enhances B cell proliferation.
        
        unable to mount Ab responses to new Ags
        
        deficient T cell help
        
        responses against T cell–independent Ags also suppressed, suggesting additional B cell defects
      - Pathogenesis of CNS Involvement
        
        MQs + cells belonging to monocyte–MQ lineage (microglial cells) are predominant cell types in infected brain; carried into brain by infected monocytes (R5 type)
        
        mechanism of damage
        
        viral products and soluble factors (e.g., cytokines such as TNF
        
        gp41-->NO induced in neuronal cells
        
        gp120: direct damage of neurons
      - Structure of HIV
        
        high variability due to relatively low fidelity of viral polymerase (1 mistake for each 100,000 replicated nucleotides) Most sequence in genome encoding the envelope GPs
        
        HIV-1: M (major) and O (outlier); M: more common form, further divided into subtypes, or clades, A through J (E spread predominantly by heterosexual contact bc of its ability to infect vaginal subepithelial DCs; B grows poorly in DCs)
    - - Parenteral: those by blood transfusion virtually eliminated bc: 1. screening for HIV Ab 2. screening for HIV-associated p24 Ag (detectable before development of Abs), 3.heat treatment of clotting factor concentrates, 4. screening on basis of history; still one in 1.5 million blood donations are HIV infected
      - Mother-to-Infant: 1. in utero (transplacental); 2. intrapartum, during delivery; 3.ingestion of HIV-contaminated breast milk; 1+2 account for most cases. higher rates of infection occur w/ high maternal viral load and/or presence of chorioamnionitis, presumably by incr placental accumulation of inflammatory cells.
      - Sexual: >75% cases; virus present in semen (EC + IC within mononuclear inflam cells): enters lacerations or abrasions in mucosa (either by direct entry into injured blood vessels / uptake into mucosal DCs); all forms of sexual transmission aided by concomitant presence of other STDs that cause genital ulcerations (syphilis, chancroid, and HSV) / by incr seminal fluid content of inflammatory cells (Gonorrhea + chlamydia); HIV also present in vaginal + cervical cells of infected women (females to males about 8x less efficient)
    - - clinical course:
        CDC classification:
        
        500 cells/µL: generally asymptomatic
        
        200-500: early symptoms
        3.<200 cells/µL: severe immunosuppression.
        
        CD4+ cell counts: status of the patient’s disease
        viral load: direction in which the disease is progressing.
        recently developed antiretroviral therapy has changed the course of the disease; doesn't eliminate all of the virus and the disease can recur if treatment is stopped
      - Clinical Features
        
        Neoplasms
        
        AIDS-defining cancers
        
        cervical carcinoma: bc of high prevalence of HPV infection. This virus is intimately associated w/ squamous cell carcinoma of cervix + its precursor lesions, cervical dysplasia and carcinoma in situ--> gynecologic examination should be part of the routine evaluation in HIV-infected women.
        
        B cell non-Hodgkin lymphomas: 2nd most common; highly aggressive, occur most frequently in severely immunosuppressed, involve many extranodal sites
        
        less common: primary effusion lymphoma, exclusively in body cavities (pleural, peritoneal, or pericardial effusions); always associated w/ KSHV, and in many cases the tumor cells are co-infected w/ both KSHV + EBV
        
        brain most common site in late stage HIV infection. ~100% of these brain lymphomas: EBV-related. In comparison only 30% to 40% of lymphomas occuring earlier are EBV-related (contribution of other factors, such as chronic B cell hyperstimulation, to lymphoma risk)
        
        Kaposi sarcoma
        
        lesions:
        -early before immune system compromised / late in advanced stages
        -(Unlike in sporadic cases) are multicentric + more aggressive; can affect skin, mucous membranes, GI tract, lymph nodes,lungs. -contain spindle cells believed to be lymphatic endothelial/ mesenchymal cells that can form vascular channels.
        -are monoclonal/ oligoclonal/ even polyclonal, an unusual feature shared by other proliferations driven by oncogenic viruses, such as certain EBV-related B cell proliferations.
        
        cause: Kaposi sarcoma herpesvirus (KSHV)/human herpesvirus-8 (HHV-8).
        mechanisms: KSHV infects lymphatic endothelial/other cells--> stimulates proliferation of endothelial cells. The KSHV genome contains homologues of several human oncogenes + cytokines contributing to growth + survival of proliferating vessels
        
        a vascular tumor that is otherwise rare; is far more common among homosexual or bisexual males than other risk groups
        
        non–AIDS-defining cancers
        
        anal cancer
        
        Hodgkin lymphoma
        
        liver cancer
        
        Opportunistic Infections
        
        CNS Involvement: At autopsy, 90% have some form of neurologic involvement, 40-60% clinically evident; in some patients neurologic manifestations may be sole/earliest presenting feature; several virally determined neuropathologic changes occur: aseptic meningitis occurring at the time of seroconversion, vacuolar myelopathy, peripheral neuropathies, and (most commonly) a progressive encephalopathy clinically designated the AIDS dementia complex
    - - IV drug abusers w/ no history of homosexual behavior (next largest group)
      - Recipients of blood (but not hemophiliacs) (1% of patients)
      - Heterosexual contacts of members of other high-risk groups (largest group in Africa and Asia)
      - Hemophiliacs (<1% of all cases)
      - Men who have sex with men (largest group)
      - in children (<13 yrs) ~1% of all AIDS cases; 90% result from from infected mother
    - - changes in tissues (except brain) aren't specific/diagnostic. In general, the pathologic features of AIDS: widespread opportunistic infections, Kaposi sarcoma, and lymphoma.
      - changes in lymphoid organs
        
        early stages: marked follicular hyperplasia (polyclonal B cell activation and hypergammaglobulinemia); sinuses: incr cellularity (primarily bc of incr MQs but also B cell lymphoblasts + plasma cells); HIV particles demonstrated within germinal centers (on villous processes of follicular DCs) Viral DNA also can be detected in MQs and CD4+ T cells.
        
        disease progression: severe follicular involution + generalized lymphocyte depletion.These “burnt-out” lymph nodes: atrophic + may harbor numerous opportunistic pathogens. presence of infectious agents may not be readily apparent w/o application of special stains; in later stages of AIDS, the spleen and thymus also appear to be “wastelands.”
        
        Non-Hodgkin lymphomas, often involving extranodal sites
        such as the brain are primarily aggressive B cell neoplasms
  - - - developmental malformation affecting 3 + 4 pharyngeal pouches, (thymus, parathyroid glands, and portions of the face and aortic arch)-->hypocalcemic tetany + additional midline developmental abnormalities
      - ppl w/ partial defects, immunity may improve spontaneously w/ age
      - extremely vulnerable to viral, fungal, protozoal, IC bacteria
    - - cause
        
        50%: X-linked; mutations in gene encoding common γ chain shared by R for cytokines IL-2, IL-4, IL-7, IL-9, IL-15; IL-7 most important bc it's the GF for survival and expansion of immature B and T cell precursors; thymus hypoplastic
        
        40-50%: auto recessive
        
        half: mutations in adenosine deaminase (ADA) involved in purine metabolism-->accumulation of metabolites-->inhibit DNA synth + toxic to lymphocytes; thymus hypoplastic
        
        other: defects in another purine metabolic pathway, primary failure of class II MHC expression, or mutations in genes encoding the recombinase responsible for the rearrangement of lymphocyte antigen-receptor genes.
      - patients may have marked lymphopenia T+B); others may have incr #s of immature T cells and/or large #s of B cells that are nonfunctional as a consequence of a lack of T cell help
      - treated by bone marrow transplantation; X-SCID is the first disease gene therapy has been used; some develop T cell leukemias bc introduced gene was inserted close to a cellular oncogene.
    - - IgM class switching
        
        certain cytokines
        
        contact-mediated signals from CD4+ helper T cells (also responsible for affinity maturation of Abs + helper T cell–mediated activation of MQs, the central reaction of cell-mediated immunity)
        
        CD40 molecules on B cells
        
        CD40L (CD154) on activated helper T cells: most common (70%) genetic abnormality, X-linked
        
        other molecules: activation-induced deaminase
      - recurrent pyogenic infections (x IgG) + infections w/ IC pathogens normally are combated by cell-mediated immunity (ex: Pneumocystis jiroveci)
    - - mutations
        
        genes involved in TH1 responses--> susceptibility to infections w/ atypical mycobacteria (combating intracellular bacterial
        infections)
        
        Ca channel prs, and other components of T cell signaling
        
        transcription factor required for TH17 response--> fungal (and occasionally bacterial) skin infections and chronic
        mucocutaneous candidiasis (defense against fungal infections)
    - - immunologic deficits
        
        cellular: thymus initially normal, but there is progressive age-related depletion of T lymphocytes in peripheral blood + lymph nodes
        
        humoral: patients do not make effective Ab responses to polysaccharide Ags (capsules..)
        
        prone to develop malignant lymphomas
      - responsible gene encodes a pr that links several membrane Rs to cytoskeleton
        
        abnormal cellular morphology (ex platelet shape changes)
        
        defective cytoskeleton-dependent activation signals in leukocytes, w/ abnormal cell–cell adhesions + leukocyte migration
      - early death; only treatment: bone marrow transplantation
    - - Other Genetic Disorders of Innate Immunity: Mutations in TLRs and their signaling pathways quite rare; immune deficiency very restricted. (ex mutations affecting TLR3 (recognizes viral RNA)--> recurrent herpes simplex encephalitis; mutations affecting MyD88 (signaling pr)--> susceptible to bacterial infections, esp severe pneumococcal lung disease, but neither suffers from multiple disseminated infections)
      - Phagocytes: phagocyte oxidase (NADPH oxidase)--> chronic granulomatous disease; defects in integrins + selectin ligands--> leukocyte adhesion deficiencies.
      - Complement Proteins
        
        late components of classical complement pathway (C5 to C9): recurrent infections by Neisseria (gonococci, meningococci) but not by other microbes (bc Neisseria have thin cell walls--> esp susceptible to lysis by membrane attack complex)
        
        regulatory pr C1 inhibitor: generation of downstream vasoactive complement mediators-->hereditary angioedema (recurrent episodes of localized edema affecting the skin and/or mucous membranes)
        
        C1q, C2, and C4: don't cause susceptibility to infections; incr risk of immune complex–mediated disease (e.g., SLE), possibly by impairing clearance of apoptotic cells / of Ag-Ab complexes from the circulation
        
        C3: incr susceptibility to pyogenic bacteria
    - - most common of all the primary immune deficiency diseases
      - most ppl asymptomatic, but predisposed to recurrent sinopulmonary infections + diarrhea.
      - association w/ AI diseases.
    - - umbrella term (diagnosis by exclusion) for disorders w/ hypogammaglobulinemia, impaired Ab responses to infection (or vaccination), and incr susceptibility to infections.
      - clinically superficially similar to XLA, but: autosomal, onset of symptoms in 2nd/3rd decades, most have norm #s of mature B cells (plasma cells absent bc of a block in Ag-stimulated B cell differentiation (bc of intrinsic B cell defects/deficient T cell help/ excessive T cell suppressive activity))
      - prone to develop a variety of AI disorders (hemolytic anemia, pernicious anemia), as well as lymphoid tumors
    - - ok until 6 mths (bc of maternal Abs) then recurrent infections
        
        certain viral infections, esp enteroviruses
        
        Giardia lamblia intestinal protozoan usually neutralized by IgA
        
        bacterial normally cleared by opsonization... (e.g., H influenzae, Strep pneumoniae, and Staph aureus
      - replacement therapy w/ IV Ig from pooled human serum
      - AI diseases (ex RA and dermatomyositis) occur in 20% of patients