Immunology Flashcards

Question

For lymphocyte diversity how are gene segments recombined randomly

Answer 1

RAG1 and RAG2

Answer 2

No mature lymphocytes

Answer 3

molecular assays using PCR Bc each t or B cell and its colonial progeny have a unique DNA rearrangement (unique antigen receptor) For lymphoma

Answer 4

Ab Recognize MHC CD3 and zeta chain-invariant, identical in all cells

Answer 5

Peptides, lipids, small molecules, without assistance from MHC proteins On epithelial surfaces (skin, GI and urogenital tracts)

Answer 6

Some have TCR that recognize MHC like molecule CD1 But this is adaptive immunity

Answer 7

CD28 on T cell interacts with cd80/86 (b7)

Answer 8

IgM or igd

Answer 9

Turns into plasma cells

Answer 10

Iga and IgB (CD79a and CD79b) | 0invariant for transduction

Answer 11

CD40L Cd40 HyperIgM syndrome

Answer 12

This receptor can also be used by EBV to enter and infect B cells

Answer 13

APC for T cell responses Located at the right place to capture antigens-under epithelial (langerhans in skin)-interstitial of all tissues where antigens may be produced TLR and lectins Recruited to T cell zones of lymphoid organs in response to microbes

Answer 14

Lots of them needed for presenting antigens to and activating T cells

Answer 15

Found in germinal centers of of lymphoid follicles in spleen and lymph nodes Fc receptors for IgG and Receptors for c3b to trap antigens bound to antibodies or complement proteins Present and select the highest addnity B cells

Answer 16

Opsonized by igg or c3b

Answer 17

Kill virus infected cells and tumor cells

Answer 18

Azurophilic granules without prior exposure

Answer 19

CD16: an Fc receptor for IgG, lyse IgG coated cells in antibody dependent cell mediated cytotoxicity Secrete ifny for macrophage activation

Answer 20

Nk cell kids and lyse IgG coated target cels

Answer 21

Il2, il15, stimulate proliferation Il2 and il15->NK cells->il12->TH1->ifny->macrophage (classical activation) Il12 activates killing and secretion of ifny

Answer 22

New Nk cells are first defined ILC Early defense

Answer 23

A1, a2 binding groove A3 is nonpolymorphc and has a binding sitefor cd8 B2 microglobulin Cytoplasm like viral and tumor antigens

Answer 24

A1, b1 binding groove B2 binding site for cd4 Extracellular bacteria and soluble proteins

Answer 25

Codominantly from each parent

Answer 26

Transplant hard Except identical twin

Answer 27

Tgfb and il10 and antiinflammatory

Answer 28

CSF GM CSF and IL7

Answer 29

Tnf antagonists

Answer 30

Thymus and bone marrow

Answer 31

Lymph nods, spleen, mucosal and cutaneous lymphoid tissues

Answer 32

Nodes-lymph dendrites Spleen-blood macrophages and dendrites

Answer 33

Sinusoids trapped in macrophages and dendrites

Answer 34

Under epithelial of skin, GI and respiratory tracts Antigens through breach of epithelium

Answer 35

Microbial mimics called adjuvants are given with the antigen and these stimulate the innate immune response

Answer 36

Ifny is 12 —-> il2 ifny Macrophage activation and stimulate IgG production Intracellular microbes Autoimmune disease, IBD< psoriasis, granulomatous inflammation

Answer 37

Il4->4, 5, 13 ``` 5-IgA class switch, eosinophils 4->igE class switching Il13-alternate macrophage activation (tissue repair and fibrosis) ``` Stimulates igE, activation of mast cells and eosinophils Helminthis parasites Allergies

Answer 38

TGFB, il6, 1, 23->IL17, 22 Recruits neutrophils and monocytes Extracellular bacteria and fungi Autoimmune disease, chronic inflammation, psoriasis, ms

Answer 39

Require T cell help B cell ingest protein display on mhc2 Helper T cell use cd40L to help class switch and affinity maturation Ifny and il4->isotype switching

Answer 40

Mucosal epithelial

Answer 41

Transported across the placenta and immunity to newborn

Answer 42

Non protein antigens Polysaccharide and lipid antigens cant be recognized by T cells but have multiple identical antigenic determinants (epitomes) that are able to engage many antigen receptor molecules on each B cell and initiate process of B cell activation NO IMMUNOGLOBULIN ISOTYPE SWITCHING AND AFFINITY MATURATION Mainly igM

Answer 43

IgE, TH2, mast, and other leukocytes Il4-IgE and TH2 Il5-eosinophils Il13-enhance IgE and stimulate mucus

Answer 44

Presensitized

Answer 45

Vasodilation, vascular leakage, congestion, edema Minutes after exposure and subsides in a few hours

Answer 46

Epinephrine

Answer 47

2-24 hours lasts for days Allergic rhinitis and bronchial asthma Eosinophils, neutrophils, basophils, monocytes, and cd4, tissue destruction

Answer 48

Eosinophils

Answer 49

Mast-tissue Basophils-circulating counterpart

Answer 50

Cross link igE FceR1 receptors C2a and c5a

Answer 51

Sensitized

Answer 52

Cd4 activated by a DC and release Il4, get TH2 and il4, 5, 13 4-IgE and TH2 50development and activation eosinophils 13-igE enhance and mucus, TH2, mast, and epithelial cells make chemokine attract th2 and other leukocytes which sensitize mast cells so the next time mast cells exposed to antigen get IgE crosslinks and activation

Answer 53

Epinephrine

Answer 54

Vasoactive amine: histamine Enzymes:neutral proteases (Chumash trypatase) and acid hydrolase)

Answer 55

Sm contraction, vascular permeability, and increased secretion Epinephrine counteracts histamine A1 agonist, beta 1 agonist, beta 2 agonist

Answer 56

Heparin; anticoagulant Chondriotin sulfate

Answer 57

Arachidonic acid derived Reactions in mast cell membranes lead to activation of phospholipase a2, converts membrane phospholipids to aa which is converted to leukotrienes and prostaglandins

Answer 58

Most potent vasoactive and spasmogenic agents

Answer 59

Highly chemotactic for neutrophils, eosinophils, and monocytes

Answer 60

Abundant, causes intense bronchospasm and increased mucus secretion

Answer 61

Platelet aggregation, release of histamine, bronchospasm, increased vascular permeability and vasodilation. Not derived from aa

Answer 62

Tnf il1 and chemokine Leukocyte recruitment , epithelial damag, Il4-amplifies th2 Response

Answer 63

Preformed0histamine, neutral proteases, proteoglycans Secondary mediators-leukotrienes, prostagladin D2, PAF Cytokines-tnf il1, il4 chemokine

Answer 64

Histamine and leukotrienes

Answer 65

Cytokines and chemokines

Answer 66

Leukocytes (eosinophils) don need additional triggering antigen Major cause of symptoms

Answer 67

Proeolytic enzymes, major basic protein, eosinophil cationic protein

Answer 68

Anti inflammatory

Answer 69

Only intermediate reaction

Answer 70

More IgE and IL4 producing TH2 cells

Answer 71

Exposure to pollutants trigger

Answer 72

No th2 or ige Mast cells abnormally sensitive to activation by nonimmune stimuli

Answer 73

Minutes, vascular shock, widespread edema, and difficulty in breathing Sensitized individuals

Answer 74

IgM and IgG promote lysis or phagocytosis and injure tissue Complement activation Antibody dependent cellular cytotoxicity

Answer 75

cells coated with IgG antibody are killed by a variety of effector cells, mainly NK cells and macrophages, and cell lysis occurs without phagocytosis MOA: When antibody is directed at a parasitic infection, there if Fc receptor-mediate inflammation and phagocytosis, characteristic of ADCC. IgG and IgE antibodies bearing Fc receptors coat the parasite. Macrophages, natural killer cells, and neutrophils can then recognize the Fc receptor and destroy the antibody-coated target cells. contribution of ADCC to hypersensitivity diseases is uncertain

Answer 76

Transfusion, hemolytic disease of newborn , autoimmune hemolytic anemia, agranulocytosis and thrombocytopenia

Answer 77

cells from an incompatible donor react with and are opsonized by preformed antibody in the host. Pink-colored urine == hemolysis; RBCs are prone to hemolysis by antibody mediated activation of complement ** this was a CIS question

Answer 78

(erythroblastosis fetalis): maternal IgG anti-erythrocyte antibodies cross the placenta and cause destruction of fetal red cells

Answer 79

a: individuals produce antibodies to their own blood cells, which are then destroyed

Answer 80

when antibodies deposit in fixed tissue (i.e. basement membrane and ECM), tissue injury is due to inflammation deposited antibodies activate complement --> C3a and C5a --> leukocytes --> lysosomal enzymes (i.e. proteases) --> ROS Responsible for tissue injury in some forms of: Glomerulonephritis Vascular rejection in organ grafts Others

Answer 81

antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation Myasthenia gravis Antibodies reactive with acetylcholine receptors in the motor end plates of skeletal muscles act as antagonists block neuromuscular transmission → muscle weakness Graves disease Antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells act as agonists stimulate the cells → hyperthyroidism ^^ these are referred to as "anti-receptor

Answer 82

IgG and IgM antibodies bind antigens usually in the circulation, and the antigen-antibody complexes deposit in vessel walls and induce inflammation (vasculitis

Answer 83

Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition Typically in vessel walls (vasculitis

Answer 84

Kidney (glomerulonephritis) Joints (arthritis) ^^ organs where blood is filtered at high pressure to form other fluids, like urine and synovial fluid, are sites where immune complexes become concentrated and tend to deposit Small blood vessels (vasculitis

Answer 85

Immune complex-mediated diseases tend to be systemic Acute Serum Sickness == prototype of a systemic immune complex disease this happens when you are given anti-serum derived from animal sources -- single large exposure to antigen i.e. serum from immunized horses was used for protection against diphtheria i.e. rattlesnake antidote patient receives antibodies from other individuals or species lesions tend to resolve as a result of catabolism of the immune complexes chronic serum sickness: results from repeated or prolonged exposure to an antigen Systemic Lupus Erythematous: associated with persistent antibody responses to autoantigens

Answer 86

formation of immune complexes introduction of protein antigen --> host response to make antibodies ~1 week after introduction, antibodies are secreted into the blood where they react with antigen that is still present --> antigen/antibody complex deposition of immune complexes circulating antigen/antibody complex are deposited in various tissue complexes that are of medium size and formed in slight antigen excess are most pathogenic inflammation and tissue injury after deposition --> acute inflammatory reaction ~10 days s/p antigen introduction fever, urticaria, arthralgia (joint pain), lymphadenopathy, and proteinuria

Answer 87

Arthus Reaction: localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin produced experimentally by intracutaneous injection of antigen in a previously immunized animal that contains circulating antibodies against the antigen As the antigen diffuses into the vascular wall, it binds the preformed antibody and large immune complexes are formed locally

Answer 88

Complement-fixing antibodies (i.e., IgG and IgM) Induce the pathologic lesions of immune complex disorders Complement proteins can be detected at the site of injury Consumption of complement proteins during active phase → decreased serum levels of C3 serum C3 levels can be used to monitor disease activity

Answer 89

appear as fibrinoid necrosis (smudgy, eosinophilic area of tissue destruction of vessel walls) when deposited in the kidney, complexes can be seen on immunofluorescence microscopy as granular lumpy deposits of immunoglobulin and complement electron microscopy as electron-dense deposits along the glomerular basement membrane

Answer 90

sensitized T lymphocytes (TH1 and TH17 cells and CTLs) are the cause of tissue injury Caused by inflammation resulting from cytokines produced by CD4+ T cells and cell killing by CD8+ T cells

Answer 91

Activation of CD4+ T Cells Naive CD4+ T cells recognize peptides displayed by dendritic cells and secrete IL-2 to stimulate proliferation of antigen-responsive T cells Antigen-stimulated T cells differentiate to TH1 or TH17 cells based on the cytokines produced by APCs IL-12 --> TH1 --> IFN-γ --> more TH1 IL-1, IL-6, and IL-23 --> TH17 Responses of Differentiated Effector T Cells Repeat exposure to antigen causes TH1 cells secrete cytokines (mainly IFN-γ) which are responsible for many of the manifestations of a delayed type hypersensitivity IFN-γ-activated ("classically") macrophages: Enhanced ability to phagocytose and kill microorganisms Express more class II MHC molecules on the surface Secrete pro-inflammatory TNF, IL-1, and chemokines Produce more IL-12 which causes an amplified TH1 response Activated macrophages eliminate the offending antigen, but if activation is sustained, continued inflammation leads to tissue injury Activated TH17 cells secrete IL-17, IL-22, chemokines, and other cytokines Recruit neutrophils and monocytes to the reaction (i.e. pro-inflammatory) Produce IL-21, which amplifies the TH17 response

Answer 92

purified protein derivative (PPD, also called tuberculin), a protein- containing antigen of the tubercle bacillus, is intracutaneously injected into previously immunized individuals Previously sensitized individuals will have reddening and induration of the site appear in 8 to 12 hours and peaks at 24 to 72 hours. Clinical Morphological Changes accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules --> perivascular "cuffing" in fully developed lesions, the venules show marked endothelial hypertrophy, reflecting cytokine mediated endothelial activation

Answer 93

Persistent or nondegradable antigens (i.e. tubercle bacilli colonizing the lungs or other tissues). Infiltrate is dominated by macrophages after 2-3 weeks. Sustained activation causes macrophages undergo a morphologic transformation into epithelioid cells, large epithelium-like cells with abundant cytoplasm. A microscopic aggregation of the epithelioid cells, usually surrounded by lymphocytes, is called a granuloma. Granulomatous inflammation Associated with strong TH1-cell activation and high-level production of cytokines such as IFN-γ. can also be caused by indigestible foreign bodies, which activate macrophages, but don’t elicit an adaptive immune response

Answer 94

vesicular dermatitis thought that the environmental chemical (e.g. urushiol from poison ivy, nickel) binds to and structurally modifies self-proteins and peptides derived from these modified self-proteins are recognized by T cells that then elicit the reaction same mechanism is responsible for most drug reactions: drug alters self-proteins, including MHC molecules, and the "neoantigens" are recognized as foreign by T cells, leading to cytokine production and inflammation manifest as skin rashes

Answer 95

T cell–mediated diseases. e.g. Type 1 diabetes or graft rejection after organ transplantation. Plays a role in reactions against viruses. Some cases it is responsible for cell damage that accompanies the infection (e.g., in viral hepatitis). activated CTLs express Fas ligand Involved in killing tumor cells. Tumor-associated antigens are presented on the cell surface

Answer 96

``` I: Allergic Anaphylaxis and Atopy First and Fast, like anaphylaxis II: antiBody cyTWOtoxic (antibody mediated) III: immune Complex three makes a complex IV: Delayed Contact Dermatitis ```

Answer 97

An alteration of the body’s microbial community that decreases the pop of good bacteria and allows the bad bacteria to take over. Is implicated in: IBD, allergy, and autoimmune disease

Answer 98

Presence of an immune reaction that is specific for some self-antigen or self-tissue The reaction is not secondary to tissue damage, but rather it is the thing that is causing the tissue damage absence of another well-defined cause of disease

Answer 99

Autoimmune polyendocrinopathy Immunologic intolerance

Answer 100

Negative selection of the T cells that are developing in the thymus. Some of the T cells become TREG cells instead of being killed off to help protect against autoimmunity

Answer 101

Negative selection of developing B cells in the bone marrow. Don’t automatically die if they are self-reactive, they can undergo receptor editing to try again. They will die if the receptor editing doesn’t work though

Answer 102

Lymphocytes that recognize self-antigens are rendered functionally unresponsive if they do not receive costimulation -- anergy. T cells that recognize self-antigens receive inhibitory signals from receptors that are structurally homologous to CD28 CTLA-4: like CD28, CTLA-4 binds to B7 molecules but does not activate signaling pathways CLA-4 has higher affinity for B7 than CD28 does -- CTLA-4 is preferentially engaged when B7 levels are low there is low level constitutive expression of B7 on resting dendritic cells in normal tissues there is low level of expression of B7 on APCs that are presenting self-antigen microbial products elicit innate immune response that increases expression of B7 on APCs PD-1: binds to two ligands that are expressed on a wide variety of cells mice lacking CTLA-4 and PD-1 develop autoimmune disorders Happens when an antigen is presented to the T cells by an APC in the absence of costimulation This pathway is used by some viruses and tumors to evade immune attack. B cells can have the same thing happen too if they don’t get signals from the specific T helper cell for that antigen

Answer 103

TREG cells function to prevent immune reactions against self-antigens. anti-inflammatory functions of TREG cells: secrete IL-10 and TGF-β, express CTLA-4 TREG cells are defined by CD4+/CD25+/high levels of α chain of IL-2 receptor/FOXP3+ mutations in FOXP3 == IPEX (immune dysregulation, polyendocinopathy, enteropathy, X-linked) syndrome IL-2 is essential for the maintenance of TREG cells TREG cells play a role in acceptance/tolerance of a fetus (which is 50% foreign) The fetus displays antigens that are foreign and need to be tolerated. Placentation evolved simultaneously with ability to stably express Foxp3 transcription factor Mice: fetal antigens induce long-lived Foxp3+ TREG cells depletion of TREG cells may lead to recurrent spontaneous abortions

Answer 104

self-reactive T-cells may express pro-apoptotic member of the BCL family (Bim) without anti-apoptotic members of the family like Bcl-2 or Bcl-x (whose induction requires the full set of signals for lymphocyte activation) unopposed Bim triggers apoptosis (intrinsic/mitochondrial pathway) self-reactive T-cells may also undergo extrinsic pathway apoptosis via Fas/FasL pathway if self-antigens engage antigen receptors of self-reactive T-cells, Fas and FasL are co-expressed and lead to apoptosis self-reactive B cells may also be deleted by FasL on T cells engaging Fas on B cells Autoimmune LymphoProliferative Syndrome (ALPS): disease caused by mutations in the FAS gene

Answer 105

Testis, eye brain No communicate blood/lymph

Answer 106

self-antigens in these tissues fail to elicit immune responses and are essentially ignored by the immune system If the tissues are damaged or infected and the antigens are released, there can be prolonged tissue inflammation and injury. post-traumatic orchitis and uveitis

Answer 107

rheumatoid arthritis, type 1 diabetes, and several other autoimmune disorders encodes a protein tyrosine phosphatase said to be the gene most frequently implicated in autoimmunity LOF mutation --> excessive lymphocyte activation

Answer 108

Crohn disease cytoplasmic sensor of microbes that is expressed in intestinal epithelial and other cells disease associated variant is ineffective at sensing gut microbes, including commensal bacteria, resulting in entry of and chronic inflammatory responses against these normally well-tolerated organisms

Answer 109

multiple sclerosis and other autoimmune diseases | these cytokines may control the maintenance of TREG cells

Answer 110

he microbial antigen looks like a self-peptide. Immune response against the microbial antigens may active self-reactive T-cells Ex: rheumatic heart disease antibodies against streptococcal proteins cross-react with myocardial proteins and cause myocarditis.

Answer 111

Apoptosis of self reactive lymphocytes

Answer 112

Treg, anergy, apoptosis ,

Answer 113

This may be due to infections promoting low level IL-2 production which is essential for maintaining TREG cells

Answer 114

TH1 and 17

Answer 115

A nti-basement membrane, anti- type IV collagen

Answer 116

A nticardiolipin, anti-β2-glycoprotein "lupus anticoagulant

Answer 117

Antiphospholipid Syndrome, SLE == anticardiolipin, anti-β2-glycoprotein "lupus anticoagulant" SLE == anti-dsDNA, anti-Sm drug-induced SLE == anti-histone antibodies

Answer 118

anti-SS-A, anti-SS-B

Answer 119

= anti-U1-ribonucleoprotein

Answer 120

limited scleroderma (CREST syndrome) == anticentromeric antibody

Answer 121

Anti dna topoisomerase

Answer 122

Affects Hispanic and African American women more than white men. Involves multiple organs like the skin, joints, kidney, and serosal membranes -- hence "systemic" immune complex mediate glomerulonephritis There are many autoantibodies, particularly antinuclear antibodies. Injury is caused by deposition of immune complexes and binding of antibodies to various cells and tissues. Type III Hypersensitivity Can be acute or insidious Typically chronic, remitting and relapsing The clinical presentation is highly variable classic picture of SLE == erythematous malar facial skin rash and renal failure with proteinuria and hematuria from immune complex deposition in the glomeruli. hallmark of SLE == production of autoantibodies

Answer 123

``` Directed against nuclear antigens. 4 categories: antibodies to DNA antibodies to histones antibodies to non-histone proteins bound to RNA antibodies to nucleolar antigens ```

Answer 124

Indirect immunofluorescence There are 4 basic patterns of immunofluorescence. Diffuse: antibodies to chromatin, histones, nucleosomes, and dsDNA common in SLE Anti-centromeric: seen in systemic sclerosis, Sjogren syndrome, and other diseases Rim/Peripheral: antibodies to dsDNA and nuclear envelope proteins Speckled: antibodies to non-DNA (i.e. Sm antigen, ribonucleoprotein, and SS-A and SS-B reactive antigens) most commonly observed == least specific nucleolar: antibodies to RNA and nuclear proteins systemic sclerosis Centromeric: patients with systemic sclerosis often contain antibodies specific for centrosomes antibodies to double-stranded DNA and the so called Smith (Sm) antigen are virtually diagnostic of SLE

Answer 125

30-40% of lupus patients directed against epitopes of plasma proteins that are revealed when the proteins are in complex with phospholipids prothrombin, annexin V, β2-glycoprotein I, protein S, and protein C May cause a false-positive test result (VDRL) for syphilis. antibodies against the phospholipid-β2-glycoprotein complex also bind to cardiolipin antigen used in syphilis serology Can interfere with clotting tests such as PTT, which makes it look like there is a Lupus anticoagulant, but really patients with these antibodies are in a hypercoagulable state. elevated/prolonged PTT but hypercoag

Answer 126

Failure of the mechanisms that maintain self-tolerance. | Cause in unknown, but genetics and environment are likely

Answer 127

Evidence Increased risk of SLE in family members of patients with SLE. Higher rate of concordance (>20%) in monozygotic twins than in dizygotic twins. Specific alleles of HLA-DQ have been linked to production of anti-dsDNA, anti-Sm, and anti-phospholipid antibodies. Some patients have inherited deficiencies of early complement components (i.e. C2, C4, and C1q) which leads to impaired removal of circulating immune complexes by mononuclear phagocytes Knockout mice for C4 are prone to develop lupus-like autoimmunity Many MHC and non-MHC genes are implicated. There are susceptibility loci that encode proteins involved in lymphocyte signaling and interferon responses, but each loci is a small risk.

Answer 128

failure of self-tolerance in B cells --> autoantibodies CD4+ T-cells specific for nucleosomal antigens escape tolerance autoantibodies in SLE show characteristic of T-cell dependent increased number of follicular helper T cells have been detected in the blood of SLE patients TLR engagement may provide second signal --> B cell activation -> increased production of autoantibodies Type I Interferons: activate lymphocytes in SLE high levels of circulating Type I Interferons and a molecular signature in blood cells suggesting exposure to these cytokines has been reported in SLE patients and correlates with disease severity

Answer 129

UV light exacerbates the disease in many patients. Can induce apoptosis and alter the DNA so that it is immunogenic, perhaps due to enhanced recognition by TLRs Stimulates keratinocytes to produce IL-1 and thus modulates the immune response Gender bias Sex hormones and genes on the X chromosome independent of hormone effects Drugs can induce an SLE-like response in humans Hydralazine, procainamide, and D-penicillamine symptoms resolve once drug is withdrawn Microbiome

Answer 130

LE bodies: in tissue, nuclei of damaged cells react with ANAs, lose their chromatin pattern, and become homogenous; aka hematoxylin body LE cell: readily seen when blood is agitated in vitro; LE cell is any phagocytic leukocyte that has engulfed the denatured nucleus of an injured cell historical interest

Answer 131

elevated PTT but hypercoaguable state -- "lupus anticoagulant" recurrent spontaneous miscarriages and focal cerebral or ocular ischemia in association to lupus == secondary antiphospholipid antibody syndrome not associated with SLE == primary antiphospholipid antibody syndrome

Answer 132

Blood vessels: acute necrotizing vasculitis involving capillaries, small arteries and arterioles. characterized by fibrinoid deposits in the vessel walls chronic stages: vessels undergo fibrous thickening with luminal narrowing

Answer 133

Connective Tissue/Joints: non-erosive synovitis with little deformity (different than RA

Answer 134

up to 50% of patients have clinically significant renal involvement due to immune complex deposition that are regularly present in the mesangium or along the entire basement membrane and sometimes throughout the glomerulus more probably have asymptomatic renal involvement Both in situ formation and deposition of preformed circulating immune complexes. kidney virtually always shows some evidence of renal involvement by EM and immunofluorescence 6 patterns of glomerular disease in SLE -- not important here; comes up again in Renal II -- not important there

Answer 135

Minimal mesangial lupus nephritis. immune complex deposition in the mesangium Seen on EM or immunofluorescence only. no structural changes identified by light microscopy -- a lot like Minimal Change Disease Least common

Answer 136

mesangial proliferative lupus nephritis

Answer 137

: focal lupus nephritis. defined by involvement of <50% of all glomeruli segmental or global involvement of the glomerulus affected glomeruli == swelling and proliferation of endothelial and mesangial cells associated with leukocyte accumulation, capillary necrosis, and hyaline thrombi; also often extracapillary proliferation associated with focal necrosis and crescent formation Presentation spectrum: mild hematuria and proteinuria acute renal insufficiency red cell casts in urine common when disease is active

Answer 138

diffuse lupus nephritis. Most common and severe form of lupus defined by involvement of >50% of all glomeruli segmental or global involvement of the glomerulus affected glomeruli == proliferation of endothelial, mesangial, and epithelial cells --> lateral crescents that fill Bowman's Space subendothelial immune complex deposits may create a circumferential thickening of the capillary wall, forming "wire loop" structures on light microscopy hematuria, proteinuria, hypertension, mild to severe renal insufficiency

Answer 139

V: membranous lupus nephritis diffuse thickening of the capillary walls due to deposition of subepithelial immune complexes usually accompanied by increased production of basement membrane-like material severe proteinuria or nephrotic syndrome

Answer 140

: advanced sclerosing lupus nephritis sclerosis of more than 90% of the glomeruli End-stage renal disease

Answer 141

Characteristic "butterfly rash" in half of patients that is located on their face with the two wings being on their cheeks and maybe forehead Can also have a similar rash on their extremities and trunk urticaria, bullae, maculopapular lesions, and ulcerations also occur Exposure to sunlight incites or accentuates the erythema Histology: involved areas show vacuolar degeneration of the basal layer of the epidermis dermis: variable edema and perivascular inflammation vasculitis with fibrinoid necrosis (affects vessels) may be prominent Immunofluorescence: deposition of immunoglobulin and complement along the dermal-epidermal junction. Can also be present in uninvolved skin Also seen in scleroderma or dermatomyositis -- sensitive but not specific

Answer 142

and other serosal involvement in SLE Inflammation of the serosal membranes may be acute, subacute, or chronic. Acute: mesothelial surfaces are sometimes covered with fibrinous exudate. Later: thickened, opaque, and coated with a shaggy fibrous tissue. May lead to partial or total obliteration of the serosal cavity. There may also be pericardial and pleural effusions.

Answer 143

damage to any layer of the heart Affects about half of patients and may not be symptomatic. Myocarditis (inflammation of the myocardium) can lead to resting tachycardia and ECG abnormalities. Coronary artery disease can lead to angina or MI. especially prevalent in young patients with long-standing disease and those who have been treated with corticosteroids Valve problems (mostly to mitral and aortic) can lead to stenosis and/or regurgitation. Valvular (Libman-Sacks) endocarditis Uncommon now due to the use of steroids. also known as Nonbacterial (Sterile) verrucous endocarditis. 1-3 cm warty deposits on any heart valve, distinctively on either surface of the leaflets vegetations in infective endocarditis are larger vegetations in rheumatic heart disease are smaller and confined to the lines of closure of the valve leaflets rheumatic heart disease == molecular mimicry with streptococcal antigens

Answer 144

noninflammatory occlusion of small vessels by intimal proliferation is sometimes noted may be due to endothelial damage by autoantibodies or immune complexes

Answer 145

Splenomegaly, capsular thickening, and follicular hyperplasia. onion skin lesions: central penicillinary arteries may show concentric intimal and smooth muscle cell hyperplasia

Answer 146

Pleuritic and pleural effusions happen to about half of patients. Chronic interstitial fibrosis and secondary pulmonary HTN

Answer 147

Typically presents in young women. Course of the disease is variable and unpredictable. Presentation can be overt or subtle. butterfly rash over the face, fever, pain but no deformity in one or more peripheral joints, pleuritic chest pain, and photosensitivity Generic anti-nuclear antibodies (ANAs) found in almost every case, but these are not specific Can have renal involvement. Hematuria, red cell casts, proteinuria, and sometimes present as classic nephrotic syndrome. Increased number of infections due to immune system dysfunction or treatment with immunosuppressive drugs. disease flares are treated with corticosteroids or other immunosuppressive drugs. most common causes of death are typically from renal failure, infections, and CAD.

Answer 148

disease in which skin looks like SLE but there are no other systemic manifestations Skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border localized, deep, and scarring -- opposite of CLE Can present on any skin, but most commonly on the face and scalp. DLE is characterized by a rash similar to SLE, but with immune complex deposition only in sun-exposed areas of the skin, a positive ANA test result in a few cases, absence of anti-Sm or anti-dsDNA antibodies, and absence of serious renal disease positive for generic ANAs but antibodies to dsDNA are rarely present deposition of immunoglobulin and C3 at the dermoepidermal junction similar to SLE

Answer 149

Presents with predominant skin involvement but distinguished from chronic discoid lupus erythematosus skin rash is typically widespread, superficial, and non-scarring Most patients have mild systemic symptoms consistent with SLE strong association with antibodies to the SS-A antigen and with the HLA-DR3 genotype intermediate between SLE and lupus erythematosus localized to the skin

Answer 150

Lupus Erythematous-like syndrome can develop in patients taking a variety of drugs like hydralazine, procainamide, isoniazid, and D-penicillamine many of these drugs are associated with the development of ANAs, but most patients are asymptomatic Can also come from treatments of anti-TNF therapy which is used to treat diseases like RA and other autoimmune diseases. Affects multiple organs, but renal and CNS involvement is uncommon. disease goes away once the drug is removed anti-histone antibodies

Answer 151

Characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) due to immune destruction of the lacrimal and salivary glands by lymphocytes that eventually leads to inflammation --> tissue damage --> fibrosis

Answer 152

me when it occurs as a primary disease. more often comorbid with another autoimmune disease (secondary form

Answer 153

lacrimal and salivary glands are the main target; respiratory and gastrointestinal tracts, and vagina == also affected

Answer 154

periductal and perivascular lymphocyte infiltration of major and minor salivary ducts patients at high risk for developing B-cell lymphoma

Answer 155

C ombination of lacrimal and salivary gland inflammation and enlargement from any cause

Answer 156

antibodies against ribonucleotide proteins SS-A (Ro) and SS-B (La) are present in as many as 90% of patients sensitive but not specific serologic markers for Sjogren Syndrome pathogenesis: aberrant T cell and B cell activation are both implicated initiating trigger may be a viral infection of the salivary glands --> local cell death --> release of tissue self-antigens in susceptible individuals, self-reactive lymphocytes to these antigens may have escaped tolerance

Answer 157

Typically seen in women aged 50-60. Symptoms results from destruction of exocrine glands Keratoconjunctivitis: blurring of vision, burning, and itching; thick secretion accumulate in the conjunctival sac Xerostomia: difficultly in swallowing solid foods, decrease in taste, cracks and fissures in the mouth, dryness of the buccal mucosa. Can also have: Parotid gland enlargement. Dryness of the nasal mucosa --> epistaxis, perforated septum Recurrent bronchitis and pneumonitis. Extraglandular Disease in 33% of patients -- more common with high anti-SS-a titers Synovitis. Diffuse pulmonary fibrosis. Peripheral neuropathy. defects of tubular function (i.e. renal tubular acidosis, uricosuria, and phosphaturia) often seen and associated with tublointestinal nephritis glomerular lesions are rare (different than SLE

Answer 158

Biopsy of the lip to examine the minor salivary glands is essential for the diagnosis of Sjogren syndrome. lymph nodes are often hyperplastic Intense lymphocytic response in the involved tissues Early: mix of polyclonal B and T cells Later: a dominant B cell clone emerges and creates a marginal zone lymphoma

Answer 159

racterized by: Chronic inflammation thought to be the result of autoimmunity. Widespread damage to small blood vessels. Progressive interstitial and perivascular fibrosis in the skin (early) and multiple organs like the GI tract, kidneys, heart, muscles, and lungs later deposition of dense collagen in the dermis with virtual absence of appendages (e.g. hair follicles

Answer 160

Majority progress to death from renal failure, cardiac failure, pulmonary insufficiency, or malabsorption

Answer 161

widespread skin involvement at onset, with rapid progression

Answer 162

skin involvement is often confined to fingers, forearms, and face, with visceral involvement late. previously described as CREST Syndrome Calcinosis: calcium deposits form in the skin Raynaud phenomenon: fingers turn white after exposure to temperature changes or emotional events Esophageal dysmotility: dysphagia (trouble swallowing) due to abnormal esophageal contraction Sclerodactyly: localized thickening and tightness of the skin of the fingers and toes; often leads to atrophy of the underlying soft tissues (pressure atrophy) Telangiectasia: benign skin condition; widened venules cause threadlike red lines or patterns on the skin

Answer 163

Thought to be related to: Autoimmunity Vascular damage Fibrosis

Answer 164

Female-to-male ratio of 3 : 1. Peak incidence in the 50-60-year age group. distinctive features are the striking cutaneous changes, especially skin thickening Raynaud phenomenon. Episodic vasoconstriction of the arteries and arterioles of the extremities Seen in virtually all patients and precedes other symptoms in 70% of cases -- sensitive, not specific Dysphagia from esophageal fibrosis that leads to hypomotility. lower two-thirds of the esophagus often develops a rubber-hose-like inflexibility abdominal pain, ileus, or malabsorption syndrome with weight loss and anemia == intestinal involvement Respiratory difficulty attributable to pulmonary fibrosis as treatment of the renal crises has improved, pulmonary disease has become the major cause of death Myocardial fibrosis leading to arrhythmias or cardiac failure. Renal: Mild proteinuria (rarely severe enough to cause nephrotic syndrome) Malignant hypertension --> fatal renal failure virtually all patients have ANAs that react with a variety of nuclear antigens anti-Scl 70 == highly specific; more likely to have pulmonary fibrosis and peripheral vascular disease anticentromere == associated with CREST syndrome

Answer 165

progressive fibrosis involving the skin, GIT, and other tissues What leads to the fibrosis in scleroderma? fibrosis may be the result of activation of fibroblasts by cytokines produced by T-cells and alternatively activated macrophages What are the three hallmarks of scleroderma? chronic inflammation, widespread damage to small blood vessels, progressive interstitial and perivascular fibrosismixed CT disease-anti U1 ribonucleotide

Answer 166

A disease with clinical features that are a mixture of the features of SLE, systemic sclerosis, and polymyositis. serologically: high titers of antibodies to ribonucleotide particle-containing U1 ribonucleotide protein synovitis of the fingers Raynaud phenomenon mild myositis -- may be accompanied by a rash (dermatomyositis) renal involvement is mild good response to corticosteroids (at least in short term) Suggested that “mixed connective tissue disease” is not a distinct entity, rather different patients represent subsets of SLE, systemic sclerosis, and polymyositis. Disease can (but not always), evolve into classic SLE or systemic sclerosis (scleroderma). Serious complications: Pulmonary hypertension, interstitial lung disease, and renal disease.IgG4 related disease

Answer 167

Most often affects middle-aged and older men. 1st characterized in autoimmune pancreatitis. Now reported in virtually all organs. Mikulicz syndrome (enlargement and fibrosis of salivary and lacrimal glands), Riedel thyroiditis, idiopathic retroperitoneal fibrosis, and inflammatory pseudotumors of the orbit, lungs, and kidneys. Characterized by: Tissues infiltrated dominated by IgG4 antibody-producing plasma cells and lymphocytes (mainly T cells). Storiform fibrosis. Obliterative phlebitis. Usually increased serum IgG4. Pathogenesis unknown and unclear if it’s really autoimmune

Answer 168

Direct path and indirect

Answer 169

``` Uses the APCs from the donor. Dendritic cells in the donor organs are the most important APCs for initiating the antigraft response MHC class I presents the antigen to the CD8 cells. The CD8 cells then proliferate to attack the blood vessels in the organ to cause endothelitis or to attack things like ducts or renal tubules. MHC class II molecules presents the antigen to CD4 cells which then make IFN-γ to activate macrophages. The macrophages can then go and attack things like ducts or renal tubules. the allogeneic MHC molecules with bound peptide resemble or mimic the self MHC-foreign peptide complexes that are recognized by self MHC-restricted T cells. recognition of allogeneic MHC molecules is a cross-reaction of T cells selected to recognize self MHC plus foreign peptides Figure 6-32 donor class I and class II MHC antigens on APCs in the graft (along with costimulators) are recognized by host CD8+ T cells and CD4+ Helper T Cells CD4+ Helper T Cells proliferate and produce cytokines (IFN-γ) --> tissue damage by a local inflammatory reaction CD8+ T cells responding to graft antigens differentiate into CTLs that kill graft cells ```

Answer 170

The recipient’s APC presents the antigen to the CD4 cell which can then activate macrophages or B cells which then make plasma cells to attack the blood vessels. The recipient T lymphocytes recognize MHC antigens of the graft donor after they are presented by the recipient's own APCs The indirect pathway is similar to the physiologic processing and presentation of other foreign (e.g. microbial) antigens. The indirect pathway generates CD4+ T Cells that enter the graft and recognize graft antigens being displayed by host APCs that have also entered the graft. This is a Type IV (Delayed) Hypersensitivity CD8+ CTLs generated by the indirect pathway cannot kill graft cells because these CTLs recognize graft antigens presented by the host's APCs and cannot recognize the graft cells directly. principal mechanism of cellular rejection may be T-cell mediated cytokine production and inflammation Figure 6-32 graft antigens are picked up, processed, and displayed by host APCs and activate CD4+ T Cells CD4+ T Cells damage the graft by an inflammatory reaction and stimulate B lymphocytes to produce antibodies

Answer 171

Most commonly seen within the initial months after transplantation or if the patient stops taking their immunosuppressive regimen. Clinical and biochemical signs of organ failure. Cytokines secreted by activated CD4+ T cells. Inflammation results in increased vascular permeability and local accumulation of mononuclear cells (lymphocytes and macrophages) --> graft injury is caused by activated macrophages endothelitis with intimal injury occurs, but this can be treated with corticosteroids Ex.: Renal Transplant Acute Cellular Rejection CD3+ T-cells infiltrate the tissue and damage (tubular) epithelium by direct cytotoxicity and by release of cytokines (i.e. IFN-γ --> macrophages

Answer 172

Lymphocytes react against alloantigens in the vessel wall and secrete cytokines that induce local inflammation. may stimulate the proliferation of vascular endothelial and smooth muscle cells. Can be insidious or can be from many acute rejections that build up over time. ischemic changes with vascular narrowing, interstitial and glomerular fibrosis and blood vessel thickening occur in chronic rejection, which is generally not reversible. "intimal thickening with luminal narrowing

Answer 173

Occurs when preformed antidonor antibodies are present in the circulation of the recipient. Can develop in persons with: previous transplant, prior blood transfusions, and multiparous women. Cross-matching now makes this very rare. fibrinoid necrosis and thrombosis are typical of hyperacute rejection

Answer 174

Antidonor antibodies produced after transplantation | Initial target of these antibodies seems to be the graft vasculature

Answer 175

Usually develops insidiously. Primarily affects vascular components. antibodies are detected in the circulation but are not readily identified within the graft

Answer 176

HLA matching: In kidney transplants: substantial benefit if all the polymorphic HLA alleles are matched (both inherited alleles of HLA-A, -B, and DR). Not done for transplants of liver, heart, and lungs -- other factors override the potential benefits of HLA matching Immunosuppressive therapy (necessary but increased risk of infections) Steroids (which reduce inflammation). Mycophenolate mofetil (which inhibits lymphocyte proliferation). Tacrolimus (FK506) - inhibits T cell functions. predecessor: cyclosporine MOA: Tacrolimus --| calcineurin (phosphatase) --> NFAT --> IL-2 (T-cell growth factor) T cell- and B cell-depleting antibodies Pooled intravenous IgG (IVIG): suppresses inflammation by unknown mechanisms. Plasmapheresis: used in cases of severe antibody-mediated rejection. The plasma is taken out of the body, it is spun down and the layer containing the antibodies is removed and the rest of the plasma is placed back into the body

Answer 177

establishes latent infection in the epithelial cells of the lower genitourinary tract Can reactivate, infect renal tubules and may even cause graft failure

Answer 178

``` EBV-induced lymphomas. Human papillomavirus (HPV)-induced squamous cell carcinomas. Kaposi sarcoma (HHV8 ```

Answer 179

Used for: Hematologic malignancies. Bone marrow failure syndromes (such as aplastic anemia). Inherited stem cell defects (such as sickle cell anemia, thalassemia, and immunodeficiency states). Usually harvested from peripheral blood after they are mobilized from the bone marrow by administration of hematopoietic growth factors. Can also be obtained from umbilical cord blood of newborn infants. Most of the time, the recipient is irradiated or treated with high doses of chemotherapy to destroy the immune system then allowing the transplanted stem cells to engraft. Two problems that are unique to HSC transplantation are GVHD and immunodeficiency

Answer 180

Occurs when immunologically competent cells or their precursors are transplanted into immunologically crippled recipients. engrafted marrow is not completely matched for MHC loci and thus contains immunocompetent donor cells that can proliferate, recognize host cells as foreign, and mount an immune response against host tissue The skin, liver, and GIT epithelium are typically effected -- systemic effects The transferred cells recognize alloantigens in the host and attack host tissues. immunocompetent T-cells present in the donor inoculum recognize the recipients HLA antigens as foreign and react accordingly Seen most commonly in the setting of HSC transplantation. Rarely occurs following transplantation of solid organs rich in lymphoid cells (e.g., the liver) or transfusion of unirradiated blood. To minimize GVHD, HLA-matching with precise DNA sequencing-based methods for molecular typing is critical

Answer 181

Within days to weeks after allogeneic bone marrow transplantation. Any organ may be affected, but the majority of clinical manifestations from: Immune system, skin, liver, and intestines

Answer 182

May follow the acute syndrome or may occur insidiously. Extensive cutaneous injury, with destruction of skin appendages and fibrosis of the dermis Chronic liver disease manifested by cholestatic jaundice is also frequent -- UTAH QUESTION hyperbilirubinemia Damage to the gastrointestinal tract may cause esophageal strictures. The immune system is devastated, with involution of the thymus and depletion of lymphocytes in the lymph nodes. Recurrent and life-threatening infections. Some patients develop manifestations of autoimmunity

Answer 183

Mediated by T lymphocytes contained in the transplanted donor cells. So depletion of donor T cells before transfusion virtually eliminates the disease. Unfortunately leads to: Recurrence of tumor in leukemic patients. Deliberate induction of graft-versus-leukemia effect by infusion of allogeneic T cells used to treat chronic myelogenous leukemia that has relapse after HSC transplantation Increased incidence of graft failures. Increased rates of EBV-related B-cell lymphoma

Answer 184

Can be from: Prior treatment. Myeloablative preparation for the graft. Delay in repopulation of the recipient’s immune system. Attack on the host’s immune cells by grafted lymphocytes. Profoundly immunosuppressed Any infection. Re-activation of cytomegalovirus (CMV) especially bad --> CMV-induced pneumonitis can be fatal

Answer 185

DIRECT: host T-cells recognize foreign HLA antigens of the graft on APCs in the graft INDIRECT: host T-cells recognize foreign HLA antigens of the graft after uptake and presentation by host APCs

Answer 186

Hyperacute rejection == thrombosis, ischemic damage, and rapid graft failure

Answer 187

T cells destroy graft parenchyma (and vessels) by cytotoxicity and inflammatory reactions

Answer 188

Graft vasculature

Answer 189

Graft vasculature

Answer 190

arteriosclerosis activated T-cells secrete cytokines that induce proliferation of vascular smooth muscle cells antibodies cause endothelial injury vascular lesions + T-cell reactions cause parenchymal fibrosis intimal thickening and luminal narrowing

Answer 191

Defects in both humoral and cell-mediated immune responses. lack of T cells means you can't activate B cells Infants present with: Prominent thrush (oral candidiasis). Extensive diaper rash. Failure to thrive. Some infants develop GVHD (manifested by morbiliform rash). Maternal T cells are transferred across the placenta and attack the fetus. Extremely susceptible to recurrent, severe infections: Candida albicans, Pneumocystis jiroveci, Pseudomonas, CMV, varicella, and a whole host of bacteria. Without HSC (BMT) transplantation, death occurs within the first year of life. Gene therapy may also be possible. X-linked most common, but can also be autosomal recessive disorders. 50% of SCID cases are caused by an X-linked mutation in the common γ chain for cytokine receptors 50% of SCID cases are caused by autosomal recessive mutations in the gene encoding adenosine deaminase (ADA)

Answer 192

Failure of B-cell precursors (pro-B cells and pre-B cells) to develop into mature B cells. B cells are absent or markedly decreased in the circulation. CD19+ pre-B cells are found in normal numbers in bone marrow -- do not express BCR (Ig) Serum levels of all classes of immunoglobulins are depressed. Plasma cells are absent throughout the body. germinal centers of MALT and GALT are underdeveloped caused by mutations in a cytoplasmic tyrosine kinase called Bruton tyrosine kinase (Btk) Btk is associated with the Ig receptor complex of pre-B and mature B cells and is needed to transduce signals from the receptor. When mutated, the pre-B cell receptor cannot deliver signals and maturation stops at this stage.. T cell–mediated reactions are normal. able to handle most (but not all) viral, fungal, and protozoal infections Usually becomes apparent after ~6 months of age once maternal immunoglobulins are depleted. Recurrent Infections (ones that rely on antibodies to clear them): Bacterial infections of the respiratory tract. acute and chronic pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus normally opsonized by antibodies and cleared by phagocytes -- not in the case of agammaglobulinemia Viruses in the bloodstream or mucosal secretions. antibodies are important for neutralizing infectious viruses Enteroviruses, such as echovirus, poliovirus, and coxsackievirus. infect the GIT and disseminate to the nervous system via blood Giardia lamblia (intestinal protozoan) normally resisted by secreted IgA, causes persistent infections in persons with x-linked agammaglobulinemia ~35% develop autoimmune diseases (like arthritis and dermatomyositis). Likely from the breakdown of self-tolerance. Chronic infections may also play a role. Treatment: Replacement therapy with immunoglobulins (IVIG

Answer 193

DiGeorge Syndrome (Thymic Hypoplasia) T-cell deficiency. Results from failure of development of the third and fourth pharyngeal pouches. Gives rise to: Thymus Loss of T cell-mediated immunity. Ig levels may be normal or reduced depending on the severity of the T-cell deficiency Poor defense against certain fungal and viral infections. Parathyroids Hypocalcemia, which can lead to tetany. Some of the C cells of the thyroid. Ultimobranchial body. Congenital defects of the heart and great vessels. May also have abnormal appearance of the mouth, ears, and facies. Considered a component of the 22q11 deletion syndrome

Answer 194

Patients make IgM antibodies but cannot produce IgG, IgA, and IgE antibodies From defect in ability of helper T cells to deliver activating signals to B cells and macrophages CD40/CD40L interaction triggers Ig class switching and affinity maturation in B cells, and stimulates the microbicidal functions of macrophages CD40 on B cells, macrophages, and dendritic cells CD40L on CD4+ Helper T cells X-linked (70%) or autosomal recessive Patients present with recurrent pyogenic infections level of opsonizing IgG antibodies is low Those with CD40L mutations also susceptible to Pneumocystis jiroveci pneumonia -- intracellular organism CD40L mediated macrophage activation is a key reaction of cell mediated immunity that eliminates pneumocystis jiroveci Occasionally, IgM antibodies react with blood cells and lead to autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. RBCs are already prone to hemolysis by complement

Answer 195

Group of disorders with hypogammaglobulinemia (low Ig) Usually all antibody classes; sometimes only IgG Diagnosis requires exclusion of other diseases of decreased antibody production Sporadic and inherited forms Have normal/near-normal numbers of B cells (as opposed to X-linked agammaglobulinemia) But they aren’t able to differentiate into plasma cells Clinically resembles X-linked agammaglobulinemia -- manifestations are caused by antibody deficiency Although M=F; onset of symptoms childhood or adolescence (as opposed to X-linked agammaglobulinemia

Answer 196

Fairly common: ~1 in 600 of European descent Extremely low levels of both serum and secretory IgA Familial or acquired in association with toxoplasmosis, measles, or some other viral infection Most asymptomatic Symptomatic patients present with recurrent sinopulmonary infections and diarrhea IgA is the major antibody in external secretions, therefore, mucosal defenses are weakened and infections occur in the respiratory, gastrointestinal, and urogenital tracts. some patients also deficient in IgG2 and IgG4 -- particularly prone to infection patients have a high frequency of respiratory tract allergy and autoimmune diseases (especially SLE and rheumatoid arthritis). patients transfused with IgA-containing blood can develop severe/fatal, anaphylactic reactions, because the IgA behaves like a foreign antigen

Answer 197

X-linked -- WASP gene WASP protein believed to anchor membrane receptors to cytoskeleton components Thrombocytopenia, eczema, and recurrent infection that leads to early death. Thymus is morphologically normal but there is progressive loss of T lymphocytes in the peripheral blood and T cell zones (paracortical areas) of lymph nodes patients do not make antibodies to polysaccharide antigens patient response to protein antigens is poor IgM levels in serum are low; IgG levels in serum are normal; IgA and IgE are elevated patients prone to developing B-cell lymphomas Treatment: hematopoietic stem cell transplantation this is the only treatment

Answer 198

Autosomal-recessive; chromosome 11, ataxia telangiectasia mutated (ATM) protein ATM is a sensor of double strand breaks in DNA; phosphorylates (activates) p53 ATM contributes to the stability of DNA double-strand break complexes during V(D)J recombination Abnormal gait (ataxia), vascular malformations (telangiectasia), neurologic deficits, increased incidence of tumors, and immunodeficiency. may affect both B and T cells defective production of isotype switched antibodies, mainly IgA and IgG2 upper and lower respiratory tract infections, multiple autoimmune phenomenon, and increasingly frequent cancers with advancing age

Answer 199

Cancer, diabetes and other metabolic diseases Complications of cancers Infections Acquired immunodeficiency syndrome (AIDS) Malnutrition Immunosuppressive therapy Irradiation Chemotherapy for cancer and other diseases

Answer 200

Caused by the human immunodeficiency virus (HIV) a retrovirus. Characterized by profound immunosuppression. Opportunistic infections, secondary neoplasms, and neurologic manifestations. By end of 2009 in US: > 1 million cases of AIDS had been reported. Ages 25-44 2nd leading cause of death in men and the 3rd for women. Global heavy burden in Africa and Asia. Rates of new infections is decreasing

Answer 201

HIV == non-transforming retrovirus of the lentivirus family Two forms (similar): HIV-1 most common in the US, Europe, and Central Africa. HIV-2 principally in West Africa and India. Virus core contains Major capsid protein p24. Most abundant viral antigen. ELISA test used to diagnose HIV infection. Two copies of viral genomic RNA. Three viral enzymes (protease, reverse transcriptase, and integrase). Core is surrounded by a matrix protein called p17. gp120 and gp41 stud the viral envelope (critical for HIV infection of cells).

Answer 202

HIV first infects T cells, dendritic cells, and macrophages (all have CD4). Establishes itself in lymphoid tissues. It can remain latent for long periods. Active viral replication → more infection of cells → progression to AIDS

Answer 203

The gp120 binds to the CD4 on a target cell which leads to conformational change that forms a new recognition site on gp120 for CCR5 and CDCR4 co-receptors chemokines sterically hinder HIV infection of cells in culture by occupying their receptors, and therefore, the level of chemokines in the tissues may influence the efficiency of viral infection in vivo The gp41 is then able to penetrate the target membrane and allow the HIV virus to fuse with the membrane and insert its RNA. The HIV RNA then uses reverse transcriptase to make a pro-viral DNA copy and insert into the target’s DNA. Then more HIV are made using the target’s machinery and the baby HIV bud off

Answer 204

HIV isolates can be distinguished by the receptor it uses: R5 strains use CCR5 Preferentially infects cells of the monocyte/macrophage lineage (M- tropic). 90% of cases, this strain dominates in acutely infected. ~1% of white Americans (rarely Africans or East Asians) are homozygous for defective copies of the CCR5 gene. Resistant to infection and the development of AIDS associated with R5 HIV isolates. ~20% of individuals are heterozygous. Onset of disease after infection is delayed. acute (early) infection is characterized by infection of memory CD4+ T-cells (which expressed CCR5) in mucosal lymphoid tissues, and death of many infected cells

Answer 205

Preferentially infect T cells (T-tropic). Even infect thymic T-cell precursors which leads to greater T-cell depletion and impairment. This strain gradually accumulates over time -- especially virulent because T-tropic viruses are capable of infecting many T-cells and even thymic T-cell precursors to cause greater T-cell depletion and impairment. R5X4 is dual-tropic and uses both

Answer 206

Dual tropic and uses both

Answer 207

Infects memory and activated T cells. Hard time infecting naive T cells. Contain an active form of an enzyme that leads to mutations in the HIV genome. APOBEC3G (for apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G). cytidine deaminase that introduces cytosine-to-uracil mutations in the viral DNA that is produced by reverse transcriptase this inhibits further DNA replication by mechanisms that are unknown Activation of T-cells converts cellular APOBEC3G into an inactive, high molecular mass complex virus can replicate in previously activated T-cells but not naïve T-cells HIV has evolved to counteract this: Viral protein Vif binds to APOBEC3G which leads to degradation by cellular proteases

Answer 208

Thrives when the host T cells and macrophages are activated by antigenic stimulation. By HIV itself. By other infecting microorganisms (like other STDs). Completion of the viral life cycle in latently infected cells occurs only after cell activation. Stimulation of cells: Ultimately leads to release of NF-κB → goes to the nucleus → increased IL-2 and IL-2R transcription, increased HIV DNA transcription can happen by environmental antigen (e.g. pollen or microbe) -- this is a physiologic response

Answer 209

Mainly by direct cytopathic effects of the replicating virus. ~100 billion new viral particles are produced every day → 1-2 billion CD4+ T cells die each day. For a while, the immune system can replace the dying T cells. But eventually, it can’t keep up. Other mechanisms also contribute to T cell death. activation induced cell death: chonic activation of uninfected cells exhausts them --> apoptosis non cytopathic (abortive) HIV infection activates the inflammasome pathway --> pyroptosis inflammatory cytokines and cellular components are released --> recruits more cells and increases the number of cells that can be infect important role in spread of the infection

Answer 210

HIV-1 can infect and multiply in terminally differentiated non-dividing macrophages. Dependent on the viral Vpr gene macrophages allow viral replication but are resistant to the cytopathic effects of HIV. May be reservoirs of infection whose output remains largely protect from host defenses May act as portals of infection. 90% of acute HIV infection is predominantly M- tropic strains

Answer 211

Mucosal dendritic cells are infected by the virus and transport the virus to regional lymph nodes Then transmitted to CD4+ T cells DCs express a lectin-like receptor that specifically binds HIV and displays it in an intact, infectious form to T cells Follicular dendritic cells (in the germinal centers of lymph nodes) Potential reservoirs of HIV Most virus particles are found on the surface of their dendritic processes Follicular DCs have receptors for the Fc portion of immunoglobulins --> trap HIV virions coated with anti-HIV antibodies trapped HIV virions retain the ability to infect CD4

Answer 212

Polyclonal activation of B cells. Characteristics Germinal center B-cell hyperplasia (particularly early in the disease course) Bone marrow plasmacytosis (high number of plasma cells in the bone marrow) Hypergammaglobulinemia Formation of circulating immune complexes -- Type III Hypersensitivity CMV, EBV, and gp41 are polyclonal B-cell activators HIV infected macrophages --> IL-6 --> B-cell proliferation most common neoplasms seen in association with AIDS are B cell non-Hodgkin lymphomas Patients with AIDS can’t mount antibody responses to newly encountered antigens. Not just because of loss of T cell help. impaired humoral immunity renders these patients prey to disseminated infections caused by encapsulated bacteria (e.g. staphylococcus pneumoniae and haemophilus influenzae) which require antibodies for effective opsonization and clearance

Answer 213

Nervous system is a major target of HIV infection. 40-60% have clinically apparent neurologic dysfunction. Infects macrophages and microglial cells. It is believed that HIV is carried into the brain by infected monocytes. Mechanism of HIV-induced damage of the brain is poorly understood

Answer 214

-- the "flu-like symptoms" Clinical presentation of the initial spread of the virus and the host response. Seen in 40-90% of individuals who acquire the virus. Typically occurs 3-6 weeks after infection. Resolves spontaneously after 2-4 weeks. Symptoms: Sore throat, myalgias, fever, weight loss, and fatigue. Rash, cervical adenopathy, diarrhea, and vomiting

Answer 215

Extent of viremia (measures HIV-1 RNA levels in the blood). viral load at the end of the acute phase reflects the equilibrium reached between the virus and the host response level of steady-state viremia (viral set point) can predict rate of decline of CD4+ T cells (i.e. progression of HIV) for clinical management, blood CD4+ T-cell counts are perhaps the most reliable short-term indicator of disease progression. For this reason, CD4+ cell counts and not viral load are the primary clinical measurements used to determine when to start antiretroviral therapy

Answer 216

Lymph nodes and the spleen are sites of continuous HIV replication and cell destruction Number of circulating blood CD4+ T cells steadily declines. Few or no clinical manifestations. Oral candidiasis (thrush), vaginal candidiasis, herpes zoster, and maybe mycobacterial tuberculosis. Autoimmune thrombocytopenia

Answer 217

Destroys the CD4+ T cells that are critical for effective immunity. Antigenic variation. Down-modulation of class I MHC molecules on infected cells. Viral antigens are not recognized by CD8+ CTLs. May also evolve and switch from relying solely on CCR5 to enter its target cells to relying on either CXCR4 or both CCR5 and CXCR4. Associated with more rapid decline in CD4+ T-cell counts

Answer 218

Typically about 7-10 years. Rapid progressors: 2-3 years. Long-term non-progressors (5-15%). Asymptomatic, stable CD4+ T cell counts, and low viremia for 10 or more years. Elite controllers (~1%) Undetectable plasma virus (<50-75 RNA copies/mL).

Answer 219

``` Fever and weight loss Diarrhea Generalized lymphadenopathy Neurologic disease Multiple opportunistic infections Secondary neoplasms ```

Answer 220

Protozoal and helminthic infections Cryptosporidiosis or isosporidiosis (enteritis) Pneumocytosis (pneumonia or disseminated infection) Toxoplasmosis (pneumonia or CNS infection) Fungal infections Pneumocystis jiroveci Candidiasis (esophageal, tracheal, or pulmonary) Cryptococcosis (CNS infection) Coccidioidomycosis (disseminated) Histoplasmosis (disseminated) Bacterial infections Mycobacteriosis Nocardiosis Salmonella infections Viral infections Cytomegalovirus Herpes simplex virus Varicella-zoster virus Progressive multifocal leukoencephalopathy via the JC virus

Answer 221

Kaposi sarcoma via the HHV8 virus (herpesvirus, KSHV) Characterized by the proliferation of spindle-shaped cells that express markers of both endothelial cells (vascular or lymphatic) and smooth muscle cells. There is a profusion of slit-like vascular spaces, suggesting that the lesions arise from primitive mesenchymal precursors of vascular channels. KS lesions display chronic inflammatory cell infiltrates (macrophages and lymphocytes) Primary lymphoma unchecked proliferation of B cells infected with oncogenic herpesviruses (i.e. EBV, HHV8/KSHV) in the setting of profound T cell depletion germinal center B-cell hyperplasia in the setting of early HIV infection majority of lymphomas seen in AIDS patients are not associated with EBV or KSHV germinal center B-cell hyperplasia increases the number of B-cells that are "at risk" for acquiring potential lymphoma initiating events Burkitt lymphoma and diffuse large B-cell lymphoma are associate with MYC and BLC6 mutations Invasive cancer of uterine cervix or anus via HPV most common neoplasms seen in association with AIDS are B cell non-Hodgkin lymphomas

Answer 222

Combination of 3-4 drugs that block different steps of the HIV life cycle. Dramatically alters the course of HIV infection and incidence of opportunistic infections and tumors. E.g. P. jiroveci and Kaposi sarcoma. Can suppress virus levels below the level of detection. Stops the loss of CD4+ T cells. Over time, peripheral CD4+ T-cell count slowly increase (often to normal). Reduced transmission of the virus. Especially from infected mothers to newborns. Concern that with more people living with HIV increased risk of spreading the infection if vigilance is relaxed. Downside of HAART Immune reconstitution inflammatory syndrome Some patients with advanced disease. Antiretroviral therapy triggers a paradoxical clinical deterioration. Occurs despite increasing CD4+ T-cell counts and decreasing viral load. Not understood why this occurs. Adverse side-effects of the drugs Lipoatrophy (loss of facial fat) Lipoaccumulation (excess fat deposition centrally) Elevated lipids Insulin resistance Peripheral neuropathy Premature cardiovascular kidney and liver disease

Answer 223

Extracellular deposits of fibrillar proteins that leads to tissue damage and functional compromise Abnormal fibrils are produced by the aggregation of misfolded proteins. Fibrillar deposits bind a wide variety of proteoglycans and glycosaminoglycans (i.e. heparan and dermatan sulfate) Associated with a number of inherited and inflammatory disorders. progressive accumulation --> encroaches on and produces pressure atrophy of adjacent cells Diagnosis usually made with tissue biopsy

Answer 224

Immunocyte dyscrasias with amyloidosis (primary amyloidosis). Associated Disease: multiple myeloma and other monoclonal plasma cell proliferations. Major fibril protein: AL amyloid light chain protein is made up of complete immunoglobulin light chains, the amino-terminal fragments of light chains, or both Chemically related precursor protein: Ig light chains (mostly λ) Reactive systemic amyloidosis (secondary amyloidosis). Associated Disease: chronic inflammatory conditions. Major fibril protein: AA. amyloid associated type of amyloid fibril protein is derived from a unique non-Ig protein made by the liver Chemically related precursor protein: SAA (serum amyloid associated, acute phase protein) In chronic inflammatory conditions (i.e. rheumatoid arthritis), the serum-associated amyloid precursor protein forms the major amyloid fibril protein AA. SAA is an acute phase reactant that increases with inflammatory conditions. CRP is also an acute phase reactant whose level is increased in inflammatory conditions, but unlike SAA, CRP does not form amyloid ``` Hemodialysis-associated amyloidosis. Associated Disease: chronic renal failure patients on long term hemodialysis for renal failure can develop amyloidosis as a result of deposition of β2-microglobulin Major fibril protein: Aβ2m Chemically related precursor protein: β2-microglobulin (part of MHC class I) Cardiac and heredofamilial forms of amyloidosis have fibrils derived from prealbumin transthyretin (TTR) senile cardiac amyloidosis resulting from deposition of transthyretin characterized by worsening congestive heart failure and pulmonary and peripheral edema; cardiomegaly Congo red-positive interstitial deposits of amorphous ```

Answer 225

amyloid is deposited in interstitial locations Plasma Cell Disorders associated with amyloid are usually systemic in nature and of the AL type malignant plasma cells synthesize abnormal amounts of a single Ig (monoclonal gammopathy) --> M protein spike on PAGE malignant plasma cells often secrete free, unpaired κ or λ light chains == Bence-Jones protein Bence-Jones proteins are excreted and concentrated in the urine free light chains are present in the serum and urine, and also deposited in the tissues as amyloid

Answer 226

autoinflammatory syndrome associated with excessive production of the cytokine IL-1 in response to inflammatory stimuli characterized clinically by attacks of fever accompanied by inflammation of serosal surfaces (i.e. peritoneum, pleura, and synovial membrane) defective gene == pyrin sometimes associated with widespread amyloidosis (AA type

Answer 227

Amyloidosis secondary to chronic inflammatory disorders: Kidneys, liver, spleen, lymph nodes, adrenals, and thyroid. Other tissues as well. Amyloidosis associated with plasma cell proliferations: More often involves the heart, gastrointestinal tract, respiratory tract, peripheral nerves, skin, and tongue. But not specific. Localization of amyloid deposits in hereditary syndromes is varied

Answer 228

Best stain for diagnosis, the protein aggregates will turn red and then look apple green on fluorescence Congo red stain under ordinary light imparts a pink or red color to tissue deposits more striking and specific is the green birefringence of the stained amyloid when observed by polarizing microscopy

Answer 229

Incidental finding with no clinical manifestations. Cause serious clinical problems and even death. Symptoms depend on the magnitude of the deposits and on the sites or organs affected. Initial clinical manifestations are nonspecific. Weakness, weight loss, light-headedness, or syncope

Answer 230

How is amyloidosis characterized? amyloidosis is a disorder characterized by the extracellular deposits of misfolded proteins that aggregate to form insoluble fibrils What are the three ways that proteins may deposit as amyloid? excessive production of proteins that are prone to misfolding and aggregation mutations that produce proteins that cannot fold properly and tend to aggregate defective or incomplete proteolytic degradation of extracellular proteins How do amyloid deposits damage tissue? pressure atrophy Do amyloids evoke an inflammatory response? No