Ch. 6: Disease of Immune System Flashcards Preview

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Flashcards in Ch. 6: Disease of Immune System Deck (156):
1

NF-kB:

when microbes are recognized, TLR’s activate this transcription factor (nuclear factor kB), which turn on production of cytokines and other microbicidial activities

- NF-kB: controls the txn of DNA --> turns on genes that keep cell proliferating and protects the cell from apoptosis
- found constitutively activated in chronic inflammation and certain cancers

2

αβ TCR

recognizes peptide Ags displayed on MHC molecules on surfaces of APC’s. The specificity of T cells for certain MHC molecules is limited, resulting in MHC restriction

TCR diversity is generated by arrangements of alpha and Beta genes

3

Rag-1 and Rag-2

(recombination activating genes) are responsible for rearrangement of Ag receptor genes of TCR’s (thus inherited defects here result in failure to generate mature lymphocytes)

4

indicator of T cell tumors?

o only T cells have the TCR rearrangement genes, thus presence of these genes is a marker of T-lineage cells
o analysis of antigen receptor gene rearrangements is a valuable assay for detecting lymphoid tumors.

5

γδ TCR

recognizes peptides, lipids and small molecules without requirement of display by MHC proteins – these are most often seen on skin and GI tracts and fn. as sentinels to protect against microbes trying to enter through epithelia

6

o CD4 and CD8:

"coreceptors” for T-cell activation - work with Ag receptor in response to Ags
• CD4 binds with class II MHC molecules
• CD8 binds with class I MHC molecules

7

types of dendritic cells?

• most important APCs for initiating primary T cell response
• Langerhans cells: APC’s that are located within epidermis
• dendritic cells are recruited to T-cell zones of lymphoid organs where they present Ags to T cells
• Follicular Dendritic Cells: dendritic cells located in germinal centers of lymphoid follicles of spleen and lymph nodes

8

NK cells? cell surface molecules?

• contain large azurophilic granules = “large granular lymphocytes”
• kill variety of infected and tumor cells
• early line of defense against viral infections and some tumors
• CD16 and CD56 surface molecules present on NK cells
-----CD16 = Fc receptor for IgG and confers NK cells ability to lyse IgG coated targets = anti-body-dependent cell mediated cytotoxicity
• NK cells secrete IFNγ → activates macrophages to destroy ingested microbes

9

what do NK cells recognize on unhealthy cells?

A. healthy cells express self-class I MHC molecules

B. Infected cells have decreased expression of Class I MHC which results in NK cells activation

10

where are B cells locatd in nodes?

o follicles: B cells located here – found in periphery of each node. Contains follicular dendritic cells.

11

where are T cells located in nodes?

o germinal centers: central region where T lymphocytes are concentrated in paracortex areas. contains dendritic cells

12

HEV's

o HEV’s: high endothelial venules: postcapillary venules where naïve T cells that have left the thymus migrate to in lymph nodes

13

Class I MHC molecules:

• expressed on all nucleated cells and platelets
• HLA-A, B, C
• display peptides that are derived from proteins – i.e. viral Ags, that are located IN the cytoplasm and usually produced in the cell
• recognized by CD8+ T cells
• proteins are degraded and transported to ER where the peptides bind newly synthesized class I molecules and are transported to cell surface to display the proteins
• The TCR of CD8+ T cells recognizes the MHC peptide complex (which will display most likely biruses or sometimes tumor cells)

14

Class II MHC

• encoded in region HLA-D: subregions HLA-DP, DQ, DR
• present Ags that are internalized into vesicles and are typically derived from extracellular microbes and soluble proteins
• internalized proteins are proteolytically digested in endosomes/lysosomes
• recognized by CD4+ T cells which fn. as helper cells
• mainly present on macrophages, B lymphocytes and dendritic cells

15

HLA B27

HLA-B27: Ankylosing Spondylitis:
•individuals who inherit this class I HLA allele have 90x greater chance of developing this disease
- inflammatory disease causing vertebra in spine to fuse together

16

IL 2

IL-2 is necessary for the growth, proliferation, and differentiation of (T cells) to become 'effector' T cells.

IL-2 is normally produced by T cells during an immune response.

Antigen binding to the T cell receptor (TCR) stimulates the secretion of IL-2, and the expression of IL-2 receptors IL-2R. The IL-2/IL-2R interaction then stimulates the growth, differentiation and survival of antigen-specific CD4+ T cells and CD8+ T cells

17

IL 4

induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4.

stimulates B cells to differentiate into IgE secreting plasma cells

18

IL 5

Through binding to the IL-5 receptor, IL-5 stimulates B cell growth and increases immunoglobulin secretion. It is also a key mediator in eosinophil activation.

19

IL 17

Interleukin 17 is a cytokine that acts as a potent mediator in delayed-type reactions by increasing chemokine production in various tissues to recruit monocytes and neutrophils to the site of inflammation, similar to Interferon gamma. IL-17 is produced by T-helper cells and is induced by IL–23 which results in destructive tissue damage in delayed-type reactions

* acts synergistically with TNF, and IL1

20

IFN gamma

IFNγ is an important activator of macrophages. Aberrant IFNγ expression is associated with a number of autoinflammatory and autoimmune diseases. The importance of IFNγ in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly from its immunostimulatory and immunomodulatory effects. IFNγ is produced predominantly by natural killer (NK)

21

signaling b/w APC's and T cells?

signal 1: binding of Ag

signal 2: APC’s express B7 proteins (CD 80/86) which are costimulators for T cells and received by CD28 receptor on naïve T cells thus provide the second signal (first being the Ag binding) to stimulate naïve T cells

22

CD40L

CD-40 ligand (CD40L): when CD4+ T cells recognize Ags being displayed on macrophages or B lymphocytes, T cells express CD40L which engages CD40 on macrophages and activates these cells

23

Th1 cells

- secretes IFNγ – potent macrophage activator – leads to destruction of ingested microbes

- stimulates IgG Ab production

host defense against intracellular microbes

24

Th2 cells

produce IL-4 – stimulates B cells to differentiate into IgE secreting plasma cells. Also produces IL-5 which activates eosinophils – leads to mast cell binding and release of histamine

- often seen in allergic reactions

25

Th17 cells

powerful recruitors of neutrophils and monocytes
- defense against extracellular bacteria and fungi

26

different types of IgG's?

IgA: secreted from mucosal epithelium
- IgG: transported across placenta, most common
- IgM: default Ab
- IgE: eosinophils cooperation to kill parasites

27

Type I

Immediate hypersensitivity

Anaphylaxis; allergies; bronchial asthma (atopic forms)

Production of IgE antibody → immediate release of vasoactive amines and other mediators from mast cells; later recruitment of inflammatory cells

Vascular dilation, edema, smooth muscle contraction, mucus production, tissue injury, inflammation

28

Type II

"antibody mediated"

Autoimmune hemolytic anemia; Goodpasture syndrome

Production of IgG, IgM → binds to antigen on target cell or tissue → phagocytosis or lysis of target cell by activated complement or Fc receptors; recruitment of leukocytes

Phagocytosis and lysis of cells; inflammation; in some diseases, functional derangements without cell or tissue injury

29

Type III

immune complex mediated

Systemic lupus erythematosus; some forms of glomer-ulonephritis; serum sickness; Arthus reaction

Deposition of antigen-antibody complexes → complement activation → recruitment of leukocytes by complement products and Fc receptors → release of enzymes and other toxic molecules

Inflammation, necrotizing vasculitis (fibrinoid necrosis)

30

type IV

cell mediated rxn.

Contact dermatitis; multiple sclerosis; type I diabetes; rheumatoid arthritis; inflammatory bowel disease; tuberculosis

•Activated T lymphocytes →
o (i) r elease of cytokines → inflammation and macrophage activation;
o (ii) T cell–mediated cytotoxicity

Perivascular cellular infiltrates; edema; granuloma formation; cell destruction

31

allergies

Type I

• Immune response is mediated by Th2 cells, IgE Abs, Mast cells
• Stimulus: ex. bee sting, food allergies, asthma
• occurs immediately after exposure to antigen, when antibody bound to mast cells in individuals is activated that has been previously sensitized to the antigen
• may cause localized cutaneous swellings, nasal discharge, hay fever, food allergy, bronchial asthma, state of shock
• Immediate or initial reaction: vasodilation, vascular leakage, smooth muscle spasm or glandular secretions (5-30 minutes)
• ¬Late Phase reaction: infiltration of tissues with eosinophils, neutrophils, basophils, monocytes and CD4+T cells and tissue destruction (2-24 hours after exposure)
• Most responses are mediated by IgE antibody-dependent activation of mast cells and leukocytes

32

activation of mast cells?

bone marrow derived cells that are activated by cross-linking of high affinity IgE Fc receptors
o anaphylatoxins = mast cell release may also be triggered by C5a, C3a
o FcεRI: Mast cells and basophils express high-affinity receptors called FceRI, that is specific for Fc portion of IgE and therefore avidly binds IgE Abs. When Ag binds IgE it results in degranulation

33

basophils

similar to mast cells however they are not normally present in tissues but circulate in the blood in extremely small numbers

34

IL 13

enhances IgE production and acts on epithelial cells to stimulate mucus secretion

35

histamine

Vasoactive amines: Histamine (*most important): histamine causes intense smooth m. contraction, increased vascular permeability and increased mucus secretion by nasal, bronchial and gastric glands, vasodilation

36

lipid mediators released by mast cells?

• Leukotrienes (C4 and D4): most potent vasoactive and spasmogenic agents known. More active than histamine and increase vascular permeability and cause bronchial smooth muscle contraction. (Leukotriene B4 is chemotactic)
• Prostaglandin D2: most abundant mediator via Cox pathway, causes intense bronchospasm and increased mucus secretion
• Platelet Activating factor (PAF): causes platelet aggregation, release of histamine, bronchospasm, increased vascular permeability, vasodilation. Also is chemotactic for neutrophils and eosinophils

37

coordination of release?

• histamine and leukotrienes are released rapidly from sensitized mast cells = responsible for intense immediate response: edema, mucus secretion, smooth mm. spasm

38

vasodilation caused by?

Histamine, PAF, Leuk C4,D4,E4, Neutral proteases, Prostaglandin D2

39

smooth muscle spasm caused by?

Luekotrienes C4,D4,E4, Histamine, Prostaglandins, PAF

40

cellular infiltration caused by?

TNF, IL-1, Leukotriene B4, Eosinophil and neutrophil chemotactic factors

41

Eosinophils

cell that is recruited to late phase reaction through eotaxin
• Eos survival is through IL-3 and IL-5
• IL-5: most potent eosinophil-activating cytokine known
• Eos liberate proteolytic enzymes and unique proteins called major basic protein and eosinophil cationic protein (both of which are toxic to endothelial cells)
• Recruited Eos cells amplify and sustain the inflammatory response without additional exposure to the triggering antigen

42

atopy

predisposition to develop localized immediate hypersensitivity reaction to a variety of inhaled or ingested allergens
o atopic individuals have a higher serum IgE levels and more IL-4 production and increase in TH2 cells compared with general population

43

opsonization and phagocytosis in type II

• cells opsonized by by IgG antibodies are recognized by phagocyte Fc receptors which are specific for Fc portions of IgG Abs
• When IgG or IgM are deposited they activate the complement pathway – generates C3b and C4b which deposit on surfaces of cells
• net result is phagocytosis of opsonized cell and destruction
• MAC complex results in membrane disruption
• antibody-dependent cellular cytoxocity (ADCC): cells that are coated with low concentrations of IgG Ab are killed by a variety of effectors cells which bind to the target – may be mediated by monocytes, neutrophils, eos, or NK cells

44

when do you see type II rxns?

1. transfusion reactions (cells from incompatible donor react with and are opsonized by preformed Ab in the host)

2. hemolytic disease of the newborn (erythroblastosis fetalis) where there is antigenic difference b/w mother and fetus, and Abs (of IgG class) from mother cross the placenta and cause destruction of fetal RBCs

3. autoimmune hemolytic anemia, agrunulocytosis, thrombocytopenia where individuals produce Abs against their own blood cells

4. drug reactions: drug acts as a “hapten” by attaching to surface molecs. of RBCs and abs are produced causing a drug-membrane protein complex

5. cellular dysfunction:
o ex: Myasthenia gravis: Abs reactive with ACh receptors in motor end plates of skeletal mm. block NT transmission and cause muscle weakness
o ex. Grave’s disease: Abs against thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate the cells resulting in hyperthyroidism

45

Autoimmune hemolytic anemia

type II
Red cell membrane proteins (Rh blood group antigens, I antigen)
Opsonization and phagocytosis of red cells

causes: Hemolysis, anemia

46

Autoimmune thrombocytopenic purpura

type II

Platelet membrane proteins (Gpllb: Illa integrin)

results in Opsonization and phagocytosis of platelets

sx: Bleeding

47

vasculitis

type II

Ags: Neutrophil granule proteins, presumably released from activated neutrophils

causes: Neutrophil degranulation and inflammation

sx: Vasculitis

48

Goodpasture syndrome

type II

ag: Noncollagenous protein in basement membranes of kidney glomeruli and lung alveoli

results in : Complement- and Fc receptor–mediated inflammation

Nephritis, lung hemorrhage

49

acute rheumatic fever

type II

Streptococcal cell wall antigen; antibody cross-reacts with myocardial antigen

Inflammation, macrophage activation

Myocarditis, arthritis

50

myasthenia gravis

type II

Acetylcholine receptor

Antibody inhibits acetylcholine binding, down-modulates receptors

sx: Muscle weakness, paralysis

51

graves disease

type II

TSH receptor

Antibody-mediated stimulation of TSH receptors

sx: Hyperthyroidism

52

insulin resistant diabetes

type II

Insulin receptor

Antibody inhibits binding of insulin

Hyperglycemia, ketoacidosis

53

pernicious anemia

type II

Intrinsic factor of gastric parietal cells

Neutralization of intrinsic factor, decreased absorption of vitamin B 12

Abnormal erythropoiesis, anemia

54

SLE

type III

Nuclear antigens

Nephritis, skin lesions, arthritis, others

55

Poststreptococcal glomerulonephritis

type III

Streptococcal cell wall antigen(s); may be “planted” in glomerular basement membrane

Nephritis

56

Polyarteritis nodosa

type III
Hepatitis B virus antigens in some cases

Systemic vasculitis

57

reactive arthritis

type III
Bacterial antigens (e.g., Yersinia)

Acute arthritis

58

serum sickness

type III
Various proteins, e.g., foreign serum protein (horse anti-thymocyte globulin)

Arthritis, vasculitis, nephritis

59

Arthus reaction

type III

Various foreign proteins

Cutaneous vasculitis

(morphologically will see fibrinoid necrosis)

60

Th1 and Th17 in type IV

• both TH1 and TH17 cells contribute to organ-specific diseases:
o TH1 cause activation of macrophages through secreting IFN gamma (stimulated by IFN gamma to differentiate). macrophages secrete IL12 which amplifies TH1 response

o TH17 cause neutrophil activation through secreting IL-17 and IL-22 (stimulated by IL-1, TGFbeta to differentiate). neutrophils produce IL-21 which amplifies TH17 response

61

tuberculin rxn

type IV response
o produced by intracutaneous injection of PPD “tuberculin”
o in previously sensitized individ. reddening and induration of site appears in 8-12 hours
o characterized by accumulation of mononuclear cells and CD4+T cells and macrophages

62

granulomatous inflammation

o activated macrophages undergo transformation into epitheloid cells
o these cells usually are surrounded by a collar of lymphocytes called “granuloma”
o associated with strong T-cell activation and is caused by foreign bodies that activate macrophages without eliciting an adaptive immune response

63

T cell killing mechanisms

important in virus infected cells

perforins and granzymes:
o preformed mediators contained in lysosome-like granules of CTLs
o perforin facilitiates release of granzymes from the complex
o Granyzmes are proteases that cleave and activate caspases and induce apoptosis of target cells

64

type I DM

type IV

T cells: Antigens of pancreatic islet β cells (insulin, glutamic acid decarboxylase, others)

Insulitis (chronic inflammation in islets), destruction of β cells; diabetes

65

MS

type IV

Protein antigens in CNS myelin (myelin basic protein, proteolipid protein)

Demyelination in CNS with perivascular inflammation; paralysis, ocular lesions

66

Rheumatoid arthritis

type IV

Unknown antigen in joint synovium (type II collagen?); role of antibodies?

Chronic arthritis with inflammation, destruction of articular cartilage and bone

67

Crohn disease

type IV

Unknown antigen; role for commensal bacteria

Chronic intestinal inflammation, obstruction

68

Peripheral neuropathy; Guillain-Barré syndrome

type IV

Protein antigens of peripheral nerve myelin

Neuritis, paralysis

69

Contact dermatitis

type IV

Various environmental antigens (e.g., poison ivy)

Skin inflammation with blisters

70

central tolerance, T cells

- process where immature self-reactive T and B lymphocyte clones that recognize self-Ags during their maturation in central lymphoid organs (ie. thymus and bone marrow) are killed or rendered harmless
- T cells:
• random somatic gene rearrangements generate diverse TCR’s, some of which recognize self
• “negative selection” when immature lymphocytes encounter self Ags in thymus they are killed. This process is responsible for eliminating many self-reactive lymphocytes from T-cell pool
• AIRE protein: “autoimmune regulator” stimulates expression of some “peripheral tissue restricted” self-ags in thymus and is critical for deletion of immature T cells specific for these Ags - mutations in AIRE cause AI disease

71

central tolerance in B cells

• when they recognize self-Ags in bone marrow they are able to undergo receptor editing and new Ag receptors are formed
• if receptor editing doesn’t occur then the cells undergo apoptosis

72

anergy

peripheral tolerance
• refers to prolonged or irreversible functional inactivation of lymphocytes, induced by encounter with Ags under certain conditions
• recognition of peptide Ag in association with self-MHC molecules on surface of APC’s requires a costimulatory second signal from APC’s. Second signals are provided by certain T cell-associated molecules such as CD28 that bind to B7 ligands on APCs
• if ag is presented by cells that do not bear the costimulators a negative signal is delivered and the cells become anergic
• the encounter b/w autoreactive T cells and their specific self-Ags displayed on dendritic cells may lead to anergy
• In anergy the cells lose their ability to trigger biochemical signals from TCR complex
• Inhibitory cells bind with CTLA-4 rather than CD28 and are thus silenced

73

PTPN-22

encodes tyrosine phosphatase - associated with rheumatoid arthritis, TI DM = “gene most frequently implicated in autoimmunity”

74

NOD-2

cytoplasmic sensor of microbes expressed in many cells – implicated in Crohn disease

75

role of infections in inducing autoimmunity....

o infections may upregulate expression of costimulators on APC’s
o “molecular mimicry” some microbes may express Ags that have the same AA sequnces as self Ags
•(ex. Rheumatic heart disease: Abs against streptococcal proteins cross-react with myocardial proteins causing myocarditis)
o tissue injury due to infections may release self-Ags and structurally alter self-Ags so that they are able to activate T cells
o paradoxically, sometimes prior exposure to infections protect against AI diseases

76

SLE characteristics

• characterized by autoantibodies that recognize ANA’s: antinuclear antibodies: directed against nuclear ags and can be grouped into four categories
• SLE starts out acutely, and becomes chronic and is characterized by febrile illness, injury to skin, joints, kidney and serosal membranes
• SLE effects women more often than men and is more predominant in black and Hispanic populations

77

Homogenous/Diffuse nuclear staining

reflects Abs to chromatin, histones and dsDNA

78

• Rim or peripheral staining:

indicates Abs of dsDNA

79

speckled pattern indirect immunofluorescence

• Speckled pattern: presence of uniform speckles, most commony seen in presence of antibodies to non-DNA nuclear constituents

80

nucleolar pattern II

• Nucloelar Pattern: presence of discrete binding to RNA

81

smith antigen

abs to dsDNA, “smith antigen” almost always diagnostic of SLE

82

antiphospholipid Abs

lupus patients also present with antiphospholipid Abs – which may give them false positive for syphilis

83

genetic inheritence of SLE?

o familial inheritance pattern
o linked with HLA-DQ: linked with anti-dsDNA and antiphospholipid antibodies
o inherited deficiencies of complement components- impairing removal of circulating immune complexes and favoring tissue deposition
o non-MHC susceptibility loci also identified

84

immunologic factors of SLE?

o defective elimination of self-reactive B cells in bone marrow – failure of self-tolerance in B cells
o CD4+ T cells specific for nucleosomal Ags that escape tolerance
o B cells specific for nuclear Ags get second signals from TLRs
o BAFF – promotes survival of B cells

85

environmental factors of SLE?

o UV light: UV irradiation induces apoptosis in cells and may alter DNA allowing for enhanced recognition by TLRs
o sex hormones
o drugs

86

presentation of SLE? need 4....

SOAP: serositis, oral ulcers, arthritis, photosensitivity
BRAIN: Blood disorders, renal disorders, antinuclear abs, immunological disorder, neurologic disorder.
MD: malar/discoid rash

87

antigens seen in majority of SLE?

anti-dsDNA

88

Ags seen in drug induced LE?

anti-histones

89

ags seen in diffuse systemic sclerosis?

Scl-70 - DNA topoisomerase I

90

ags seen in limited scleroderma - CREST

anticentromeres

91

ags seen in sjogren syndrome

SSA, SSB (RNPs)

92

ags seen in inflammatory myopathies?

Jo-1

histidyl-tRNAsynthetase

93

morphologic changes seen in SLE in kidney

• Kidney: Type III HS
o immune complex deposition (composed of anti-nuclear Abs) in glomeruli, tubular or peritubular capillary BM and larger blood vessels
o Mesangial lupus glomerulonephritis: cell prolif. and IC deposition w/out involvement of glomerular capillaries. granular mesangial deposits of Immunoglobulin and complement are always present
• Note: mesangial cells are specialized cells around blood vessels in the kidneys
o Focal Proliferative Glomerulonephritis: fewer than 50% involvement of all glomeruli
o Diffuse proliferative glomerulonephritis: most severe – pathologic glomerular changes
o Membranous glomerulonephritis: diffuse thickening of capillary walls
o “wire loop lesions” prominent thickening of capillary wall
o changes in interstitium and tubules are frequently present

94

morphologic changes seen with SLE in skin?

Type III HS
o malar erythema: seen due to exposure to sunlight
• involved areas show vacuolar degeneration of basal layer of epidermis; edema and perivascular inflammation see in dermis

95

morphologic changes seen in joints with SLE?

• Joints: Type III HS
o noerosive synovitis with little deformity seen (contrast to rheumatoid arthritis)

96

pericarditis/serosal involvement seen with SLE morphologically?

o inflammation of serosal linings – coated in shaggy fibrous tissue
• myocarditis
• nonbacterial verrucous endocarditis (warty deposits on heart valves)
• coronary artery disease

97

chronic discoid LE

disease where skin manifestations may mimic SLE but systemic manifestations are rare
• see skin plaques, edema, erythema, scaliness
• 35% of patients have positive ANA but none are dsDNA

98

subacute cutaneous LE

predominant skin involvement
• different from CDLE because skin rash is widespread, superficial and nonscarring
• have mild systemic symptoms consistent with SLE
• strong association with Abs to SS-A antigen and HLA-DR3 genotype
• b/w SLE and CDLE

99

drug induced LE

• hydralazine, procainamide, isoniazid, D-penicillamine
• drugs associated with development of ANAs
• renal and CNS involvement is not common
• high frequency of Abs for histone

100

Sjogren syndrome

• chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting in immunologically mediated destruction of lacrimal and salivary glands
• antibodies against ribo-nucleoprotein antigens are detected: SS-A (Ro) and SS-B (LA)
• increased risk of developing non-Hodgkin lymphoma
• abberent T and B-cell activation implicated: initiating trigger may be viral infection of salivary glands, causing local cell death and release of cell Ags
• EBV and Hep C virus are often initiating stimuli

101

clinical features of Sjogren syndrome?

• women of ages 50-60 years old
• keratoconjunctivitis: blurring vision, burning, itching,
• xerostomia: difficulty swallowing food, cracks and fissures in mouth
• parotid gland enlargement
• in contrast to SLE, glomerular lesions are extremely rare in this syndrome: more often see defects in renal tubular acidosis and tubulointerstitial nephritis
• biopsy of lip is necessary for dx

102

systemic sclerosis

• systemic sclerosis is chronic disease characterized by 1. chronic inflammation resulting from autoimmunity 2. widespread damage to small blood vessels 3. progressive interstitial and perivascular fibrosis in skin and multiple organs
• characterized by excessive fibrosis throughout the body: most commonly affected is skin, but also see GI tract, renal, heart, mm, and lung involvement
• in majority of patients the disease progresses to visceral involvement, with death from renal failure, cardiac and pulmonary failure

103

diffuse scleroderma

: characterized by widespread skin involvement at onset with rapid progression and early visceral involvement
--> ANA to SCL-70

104

limited scleroderma

skin involvement is confined to fingers, forearms and face and visceral involvement occurs very late
o often develops into CREST syndrome: calcinosis, raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia
--> ANA anticentromere abs

105

etiology and pathogenesis of scleroma

• Abnormal Immune Response:
o CD4+ T cells respond to Ag that accumulates in skin and release cytokines that activate inflammatory cells and fibroblasts
o TGFbeta and IL-13 stimulate txn of genes that ecode collagen and ECM proteins in fibroblasts
o almost all patients have ANA’s:

• Vascular Damage:
o microvascular disease is present early in the course and may be the initial lesion
o see capillary dilation and leaking with nailfold distorted capillary loops increased levels of vWF and increased platelet activation

• Fibrosis:
o progressive fibrosis caused by multiple abnormalities accumulating, including fibrogenic cytokines, hyperresponsiveness of fibroblasts to these cytokines and scarring following ischemic damage caused by vascular lesions

106

morphology of systemic sclerosis?

1. Skin: majority of patients have diffuse sclerotic atrophy of skin, normally beginning in fingers and progressing to shoulders, UA, face, neck
• see edema and perivascular infiltrates with CD4+ T cells
• increasing fibrosis of dermis
• in advanced stages fingers take on tapered claw like appearance with no mvmt of joints and face becomes a drawn mask, sometimes fingers undergo autoamputation

2. Alimenatary Tract: see progressive atrophy and collagenous fibrous replacement, often seen in esophagus
• lower 2/3 of esophagus has rubber hose inflexibility → gastric reflux → barrett metaplasia

3. MSK system: inflammation of synovium and fibrosis of joints

4. Kidneys: vascular lesions and interlobular aa. show intimal thickening due to deposition of collagenous material
• renal failure accounts for 50 % of death
• no specific glomerular changes

5. Lungs: pulmonary HTN and interstitial fibrosis, pulmonary fibrosis

6. Heart: pericarditis, effusion and myocardial fibrosis

107

clinical features of sclerosis?

• more common in females, seen more in blacks
• distinctive features (from rheumatoid arthritis) are striking cutaneous changes, notably in skin thickening
• Raynaud’s phenomenon: episodic vasoconstriction of aa. and arterioles in extremities
• Dysphagia: due to esophageal fibrosis
• abdominal pain, intestinal obstruction, malabosorption
• malignant HTN and fatal renal failure

108

direct pathway of graft rejection

*** acute rejeciton

• T cells of transplant recipient recognize allogenic (donor) MHC molecules on surface of APC’s in the graft
• DC’s carried in donor organs are most important APCs for initiating antigraft response – b/c they not only express high levels of Class I and II MHC molecs but also have costimulator molecs
• T cells of host encounter DC’s of grafted organ. CD8+ T cells recognize class I MHC moleces and differentiate into CTLs which can kill graft cells
• CD4+ T cells recognize class I molecs and proliferate into TH1 effector cells → they will release cytokines and trigger a delayed hypersensitivity reaction in graft, resulting in increased vascular permeability and infiltration of lymphocytes and macrophages → graft injury
• process: allogenic MHC molecs with bound peptides, resemble and mimic the self MHC foreign peptide complexes that are recognized by self-MHC-restricted T cells, thus resulting in a cross-reaction of T cells selected to recognize self-MHC foreign peptides

109

indirect pathway of graft rejection

*** chronic rejection ****
• recipient T lymphocytes recognize MHC Ags of the graft donor presented by their own APCs
• The peptides derived from donor tissue are presented by hosts own MHC molecs like a foreign peptide
• generates CD4+ T cells that enter graft and recognize graft Ags and results in delayed hypersensitivity reaction and produce T cell cytokines
• CD8+ T Cells can’t recognize or kill graft cells, thus this is not the main arm of the mechanism

110

humoral graft rejection

hyperacute rejection occurs when preformed antidonor Abs are present in circulation of recipient- i.e. they may be present in a patient who has prior rejected a kidney, prior blood transfusions, prior pregnancys

111

hyperacute rejection

within minutes-hours of transplant
• kidney rapidly becomes cyanotic, mottled, flaccid, and may excrete a few drops of bloody urine
• IgG and complement are deposited on vessel wall causing endothelial injury and fibrin-platelet thrombi
• neutrophils rapidly accumulate within aa, glomeruli, peritubular capillaries
• glomeruli undergo thrombotic occlusion of capillaries and fibrinoid necrosis occurs in arterial walls
• kidney undergoes necrosis and has to be removed

112

acute rejection

days after transplant or even months/years after immunosuppression is removed
• humoral rejection = see vasculitis
• cellular rejection = see interstitial mononuclear cell infiltrate



113

acute cellular rejection

Acute Cellular Rejection:
o seen within initial months of transplant
o mononuclear cell infiltration → focal tubular necrosis
o CD4+ and CD8+ T lymphocytes r=present
o endothelitis: CD8 cells damage vascular endothelial cells
o patients respond well to immunosuppression if this is only type of rejection present (i.e. Cyclosporine)

114

acute humoral rejection

Acute Humoral rejection (rejection vasculitis):
o mediated by antidonor Abs and causes damage to blood vessels: vasculitis
o see extensive necrosis of renal parenchyma – mimics atherosclerotic thickening
o treat with B cell depleting agents

115

chronic kidney rejection

progressive renal failure manifested by rise in serum creatinine 4-6 mos after implant
• vascular changes: dense fibrosis in cortical aa. results in renal ischemia, glomerular loss, interstitial fibrosis and tubular atrophy and shrinkage of renal parenchyma. See renal HTN, doesn’t respond well to treatment

116

cyclosporine

• immunosuppressive therapy through cyclosporine
o works by clocking activation of txn factor called NFAT which is reqd for txn of cytokine genes, in particular IL-2

117

azathioprine

inhibits leukocyte development from bone marrow precursors

118

rapmycin

: inhibits lymphocyte proliferation

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graft versus host disease

o occurs in any situation in which immunologically competent cells are transplanted into immunologically crippled recipients and the transferred cells recognize alloantigens in the host
o most often seen in bone marrow transplants
o immunocompetnt T cells present in the donor marrow recognize the recipients HLA Ags as foreign and react against them
o thus to minimize this they often do HLA matching

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acute GVH disease

o days to weeks after bone marrow transplantation
o involves immune system and epithelial of skin liver and intestines
o see generalized rash, desquamation
o thought damage is inflicted by cytokines released by sensitized donor T cells

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chronic GVH disease

o extensive cutaneous injury, destruction of skin appendages, fibrosis of dermis (may resemble systemic sclerosis)
o chronic liver disease
o devastated immune system – can get life-threatening infections
o depletion of donor T cells prior to transplantation virtually eliminates the problem! however, with their elimination you see graft-versus-leukemia effects, increased EBV and B-cell lymphoma

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X Linked Agammaglobulinemia (Bruton’s Agammaglobulinemia):

• B cells are absent → no production of Abs: failure of B-cell precursors to develop into mature B cells (no pro-B to pre-B cells)
• functional IgG genes are not expressed
• due to mutation in Bruton tyrosin kinase (Btk): a cytoplasmic tyrosin kinase found on long arm of X at Xq21.22
• clinically disease affects male infants who have recurrent infections beginning at 6 mos of age (loss of maternal IgG immunity)
• present w/ viral infections of pharyngitis, otitis media, bronchitis, pneumonia: H. influenza, S. pneumococcus, S. aureus, G. lamblia

Immunologic findings:
• B cells are absent: Pre-B cells which express marker CD19 but not membrane Ig are found in normal numbers
• germinal centers are underdeveloped
• Plasma cells are absent
• T cell-mediated rxns are normal

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Common Variable Immunodeficiency

• a group of disorders characterized by B-cell maturation defect and hypogammaglobulinemia
• clinically both sexes are affected with onset in childhood of recurrent bacterial infections and increased susceptibility to G. lamblia. recurrent pyogenic infections
• complications include increased frequency of developing AI diseases and increased risk of non-Hodgkin lymphoma and gastric cancer
• abnormality is due to BAFF receptor
Immunologic findings:
• have nomal numbers of B cells, however they aren’t differentiated into plasma cells

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Isolated IgA deficiency:

no IgA
• defect in impaired differentiation of naïve B cells to Ig-A producing cells
• see recurrent sinopulmonary infections, diarrhea, respiratory tract allergies

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Hyper-IgM Syndrome

no IgG, IgA, IgA
• make IgM Abs but defect affects ability of helper T cells to deliver activating signals to B cells and macrophages
• action of CD4+ T helper cell reqs engagement of CD40 on B cells and CD40L on DC’s – this triggers Ig class switching and affinity maturation of B cells
• mutations in gene encoding CD40L on Xq26
• see recurrent pyogenic infections, and pneumonia
Immunologic findings:
• elevated IgM but no IgA, IgE or IgG
• number of B and T cells is normal
• many IgM Abs react with blood → autoimmune hemolytic anemia

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DiGeorge Syndrome (Thymic Hypoplasia

• T-cell deficiency that results from failure of development of third and fourth pharyngeal pouches: results in no Parathyroid glands and no thymus
• see hypocalcemia, tetany, T-cell deficiency, recurrent infections with viral and fungal organisms, congenital defects of heart and great vessels, facial deformities
• T cell zones – paracortical area of lymph tissues – are depleted and there are decreased Ig levels
• mutation: deletion of 22q11

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Severe Combined Immunodeficiency: (SCID)

• combined deficiency of both cell-mediated and humoral immunity that is often caused by a stem-cell defect or a defect in the T-cell population
• infants present with thrush (oral candidas) diaper rash, and failure to thrive
• Clinical features: recurrent infections with bacteria, fungi, protozoa; susceptibility to Candida cytomegalovirus (CMV), pneumocytosis carinii infections.
• treated with stem cell transplant- most infants die in a year if not treated

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X linked SCID

X-linked SCID: mutation in cytokine receptor subunit→ defect in T cell development
o T cell numbers are depleted, and B cells are normal, but there is little Ab synthesis b/c T cells are impaired

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autosomal SCID

Autosomal SCID: deficiency in enzyme adenosine deaminase (ADA)
o leads to accumulation of toxins that damage T cells
o thymus is small and devoid of lymphoid cells

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Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome)

• X linked recessive disease with mutations in Wiskott-Aldrich syndrome protein (WASP)
o thought to be needed for cytoskeletal dependent responses
• clinical triad: recurrent infections, severe thrombocytopenia, eczema (chronic spongiform dermatitis)
• thymus is normal, but there is progressive depletion of T lymphocytes and loss of cellular immunity
• IgM levels are low, but IgG are normal, IgA and IgE are paradoxically elevated
• Tx: bone marrow transplantation
• complication: increased risk of non-Hodgkins lymphoma and death due to infection and hemorrhage

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Genetic Deficiencies of Complement System:

• C2 deficiency: most common
o see increased incidence of SLE-like AI diseases
o alternative pathway takes over to control infections
• C3 deficiency: very serious
o C3 is needed for classical and alternative pathways – results in serious recurrent infections
• deficiency in C1 inhibitor: hereditary angioedema

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structure of HIV

• spherical with e- dense, cone-shaped core surrounded by lipid envelope derived from host cell membrane
• virus core contains:
o major capsid protein: p24
o neucleocapsid protein p7/p9
o two copies of genomic RNA
o three viral enzymes (protease, reverse transcriptase, integrase)
• viral core is surrounded by matrix protein called p17
• virion envelope is studded with gp120 and gp 41 which are critical for HIV infection of cells
• genome contains: gag, pol, env genes

* note: anti-HIV-1 protease inhibitor drugs prevent viral assembly by inhibiting formation of mature viral proteins

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pathogenesis of HIV

• two main targets: immune system and CNS
• severe loss of CD4+ T cells as well as imipairement of helper T cells as well as macrophages and dendritic cells
• HIV enters through mucosal tissues and blood and first infects T cells as well as DCs and macrophages

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mechanism of infection of HIV

• uses CD4 molecule as receptor and chemokines as coreceptors
• HIV gp120 binds CD4 cell
• binding leads to conformation change resulting in gp120 binding to coreceptors CCR5 and CXCR4
• binding to coreceptors causes conformation change in gp41 reulting in exposure of hydrophobic region called “fusion peptide at tip of gp41”: gp41 inserts into cell membrane of targets, leading to virus fusion
• after fusion the virus core enters the cytoplasm
• note: chemokines bind to the same receptors, thus increased chemokines in vivo may decrease efficiency of viral infection

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how does HIV replicate?

• RNA genome undergoes reverse transcription leading to synthesis of complementary dsDNA (cDNA)
• to integrate into genome, the cell must be dividing, cDNA circularizes and enters nucleus and is integrated
• HIV infects memory and activated T cells but cannot infect naïve T cells b/c they contain an active form of an enzyme that introduces mutation in HIV genome (called APOBEC3G) – introduces cytosine-to-uracil mutations
o activation of T cells inactivates this enzyme, and allows for HIV infection subsequently
• virus activation results in cell lysis
• long terminal repeat sequences flanking the HIV genome contain NF-kB binding sites that can be triggered by cytokine txn factors – thus induction results in pathological outcome
• HIV thrives when host T cells and macrophages are physiologically activated = subversion from within

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Vpr protein

o HIV can infect and multiply in terminally differentiated nondividing macrophages due to Vpr protein which allows nuclear targeting of HIV preintegration complex through nuclear pore
o Infected macrophages bud small amounts of virus from cell surface, but contain large amounts of particles in intracellular vacuoles – thus providing a reservoir
o In late stages of HIV infection when CD4+ T cells decline, macrophages may be site of continued viral replication
o uninfected monocytes show decreased microbicidal activity, decreased chemotaxis, decreased
o secretion of IL1 and TNF

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DC infection via HIV

• Mucosal Dendritic Cells:
o infected by virus and transport it to regional lymph nodes where it is transported to CD4+ T cells

• Follicular DC’s:
o in germinal centers of lymph nodes can also be reservoirs for HIV
o they trap the HIV virions, but when they come into contact with CD4+ T cells they can infect them

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Primary Infection and Acute Retroviral syndrome


> 500 cells/uL = Acute HIV syndrome

• infection of CD4+ T cells which express CCR5 along with mucosal infection of lymphoid tissues
• mucosal infection is followed by dissemination of virus and development of host immune responses:
o DCs in epithelial capture virus and migrate to lymph nodes where it is passed to CD4+ T cells
o viremia: within days see high number of HIV particles in patient’s blood
• virus disseminates to other tissues
• HIV-specific CD8+ T cells are detected in blood at time viral titers begin to fall and likely responsible for initial containment of HIV infection
• acute retroviral syndrome: clinical presentation of initial spread of virus and host response
o occurs 3-6 weeks after infection
o see acute illness, sore throat, myalgias, fever, weight loss, fatigue
o extend of viermia, measured as HIV-1 RNA levels is useful as marker of HIV disease progression

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Chronic Infection: Phase of clinical latency

200-499 cells /uL = clinical latency

• lymph nodes and spleen are sites of continuous HIV replicaton and cell destruction
• no clinical manifestations of HIV present at this time – frequency of infected circulating cells remains low, while many more are infected in replication sites

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AIDS

• fever, W/L, diarrhea, lymphadenopathy, opportunistic infections, neurologic disease, secondary neoplasm

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opportunuistic infections in AIDS

account for majority of death in untreated patients
• pneumonia
• Herpes simplex virus: ulcerations of mouth, esophagus, genitalia
• Candidiasis: most common fungal infection
• Cytomegalovirus: effects eye and GI tract
• Atypical mycobacteria: Tuberculosis
• Cryptococcosis: meningitis
• Toxoplasma gondii: affects CNS
• Salmonella, persistent diarrhea

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Kaposi Sarcoma

- tumor seen w/ AIDS
non-Hodgkin B-Cell lymphoma, cervical cancer in women and anal cancer in men
o caused by oncogenic DNA viruses: herpes virus, HPV, and EBC
o vascular tumor characterized by proliferation of spindle-shaped cells
o commonly involves skin, GI tract, lymph nodes, lungs

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• Lymphomas seen with AIDS

o systemic lymphomas:
o CNS lymphomas:
o body cavity lymphomas:

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Amyloidosis

= a group of diseases characterized by deposition of extracellular protein due to abnormal folding of proteins, which are deposited as fibrils in extracelluar tissues and disrupt normal function
•Common Features of Amyloid:
o individual molecular subunits form Beta-pleated sheets
o amorphous eosinophilic extracellular deposits seen
o deposits stain red with Congo Red Stain
o deposits have apple green bifrengence under polarized light
•Composition of Amyloid:
o fibrillary protein that varies with disease

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AL particles

AL (amyloid light chain) particle: derived from plasma chains – seen in plasma cell tumors

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AA particles

o AA (amyloid associated): non-Ig protein synthesized in liver – seen in chronic inflammation

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Abeta particles

o β-amyloid protein (Aβ): seen in Alzheimers disease

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ATTR

o Transthyretin (TTR): seen in senile systemic amyloidosis

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β2 Microglobulin:

seen with longterm hemodialysis

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primary amyloidosis

amyloid light chain (AL) amyloid, whose fibrillary protein is made of kappa or lambda light chains
a. seen in plasma cell disorders (like multiple myeloma and B-cell lymphomas)

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secondary amyloidosis

2. Reactive Systemic Amyloidosis (Secondary Amyloidosis): amyloid associated amyloid (AA) whose fibrillary proteins is serum amyloid A (SAA), an acute phase reactant produced by liver which is elevated with ongoing chronic inflammation and neoplasia
a. seen with chronic disease, rheumatoid arthritis, SLE, TB, bronchiectasis, osteomyelitis, Crohn’s disease, cancer

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familial mediterranean fever

has type AA amyloid with fibrillary protein composed of SAA. This autosomal recessive disease is characterized by recurrent inflammation, fever, and neutrophil dysfunction

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Hemodialysis-associated amyloidosis

: has Aβ2M type amyloid with fibrillary protein composed of β2-Microglobulin
a. may cause carpal tunnel and joint disease

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Senile Cerebral Amyloidosis (Alzheimers disease):

has Aβ amyloid with protein composed of β-Amyloid precursor protein (βAPP)
a. found in Alzheimers plaques and cerebral vessels

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Senile Cardiac/Systemic Amyloidosis:

has ATTR type amyloid with fibrillary protein composed of transthyretin
a. seen in men older than 70 and may cause heart failure as a result of restrictive cardiomyopathy

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morphology of amyloidosis

• Kidney: see shrunken due to ischemia, thickening- many different problems!
• Spleen: splenomegaly with
o tapioca-like granules on gross inspection = sago spleen
o lardarceous spleen = maplike areas of amyloidosis
• Liver: hepatomegaly, deformity, pressure atrophy, disappearance of hepatocytes
• Heart: enlarged and firm, pressure atrophy of myocardial fibers
• Tumor forming amyloid on tongue