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MI Immuno/Heme > Pre-existing innate immunity > Flashcards

Pre-existing innate immunity Flashcards

1
Q

What lineage are NK cells derived from?

A

Lymphoid lineage (as are T and B cells)

However, unlike T/B cells, NK cells do not react to specific pathogens

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2
Q

How do NK cells recognize intracellular pathogen-infected cells or tumor cells?

A

By using the imbalance between target cell surface MIC (higher) and MHC class I proteins (lower)

Or the presence of IgG bound to the target cell surface

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3
Q

How do NK cells kill target cells?

A

By using perforin and granzyme to induce target cell apoptosis

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4
Q

What type of molecular signals do neutrophils respond to?

A

PAMPs and chemokines

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5
Q

What is typically the first leukocyte to enter an infection site?

A

Neutrophils

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6
Q

Function of activated neutrophil

A

Killing extracellular microbial pathogens:

Adhere and phagocytose unicellular microorganisms - afterward - cytoplasmic ganules fuse w/ the phagosome and the microorganism is killed by anti-microbial effectors

Also kills by releasing granule contents and reactive chemical species into the extracellular milieu to kill non-phagocytosed pathogens at site of infection (also contributes to tissue damage)

Stimulate wound healing

Major innate immune cells that kill unicellular bacteria and fungi

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7
Q

Does a neutrophil restore its granules after discharging?

A

No, once they are fully discharged, the nuetrophils die

Dead neutrophils contribute to the formation of pus

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8
Q

Band cells

CBC

A

Immature neutrophils

Increased band cells (left shift) indicate the a Pt has suffered a strong, often acute, inflammatory/infectious insult

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9
Q

Seg cells

CBC

A

Mature neutrophils

Increased segs often indicates ongoing bacterial or fungal infection

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10
Q

Macrophages

A
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11
Q

How do neutrophils and macrophages differ in function?

A

Macrophages continuosly recharge their lysosomes w/ anti-microbial compounds and do not die after killing microorganisms

Macrophages also bind both PAMPs and DAMPs

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12
Q

What is the fate of the phagosome after neutrophils/macrophages ingest a pathogen?

A

Fusions with the lysosome to kill pathogen with toxic lysosomal contents

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13
Q

Endocytic PRR’s expressed by macrophages/neutrophils

A
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14
Q

Opsonins

A

Bind to microbial surfaces, including encapsulated microbes

IgG and C3b are important opsonins

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15
Q

Mucus

A

Branched glycoprotein polymer made by mucosal goblet cells

Major function - retain water and keep mucosal epithelium moist

Binds IgA and anti-microbial peptides (AMPs)

IgA - neutralizes

AMPs - kill

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16
Q

What activates neutrophils?

A

Local inflammation induced by PAMP stimulated macrophages and mucosal epithelia

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17
Q

Pseudomembranous enterocolitis

A

C. diff secretes toxin that compromises integrity of the gut lining

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18
Q

Cationic anti-microbial peptides

A

Defensins
Histatins
Cathelicidins

Found in sweat, tears, and mucosal secretions

Many secreted by mucosal epithelium and Paneth cells

Others are made by macrophages and neutrophils

Forms pores and cause osmotic lysis of target cells

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19
Q

C-reactive protein

A

CRP - secreted from the liver into the blood/lymph and opsonizes pathogens

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20
Q

Lysozyme

A

Enzyme that degrades PPG

Found in tears, saliva, CSF, and is secreted by mucosal Paneth cells

Neutrophils also release lysozyme into tissues when they migrate to site of infection

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21
Q

Complement pathways

A

Alternative path

Lectin path

Classical path

Initiated differently but all three merge at the step where the C3 complement protein is cleaved into fragments C3a and C3b

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22
Q

C3b

A

Chemically reactive opsonin (macrophages and nuetrophils have surface C3b receptors)

Binds to pathogen surface and marks it for destruction - opsonization or stimulation of the membrane attack complex (MAC)

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23
Q

Pro-inflammatory mediators of the complement pathway

A

C3a

C4a

C5a

Induce inflammation in infected tissues where the cascades are activated

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24
Q

What activates the classical complement pathway?

A

Antibody or CRP binding to the surface of a pathogen

CRP binds to phosphocholine in bacterial and fungal cells walls (not to human phosphocholine)

At least two adjacent Ab Fc regions are required for activation - 1 IgM pentamer, 2 IgG molecules, or CRP bind to complement factor C1qrs

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25
Q

C1qrs

A

Binds to IgG, IgM, or CRP

Cleaves C4 and C2 into their a/b componenets

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26
Q

C4b

A

Binds to the pathogen surface, then binds C2a forming the classical C3 convertase (C4b2a)

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27
Q

Classical C3 convertase

A

C4b2a - cleaves C3 into its a/b componenets

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28
Q

C3b

A

Binds to the target cell surface to either acts as an opsonin or to complex w/ the classical C3 convertase to form the classical C5 convertase (C4b2a3b)

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29
Q

Classical C5 convertase

A

C4b2a3b - cleaves C5 into a/b components to start MAC formation

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30
Q

What activates the lectin complement pathway?

A

Mannose binding lectin (MBL) binding to mannose-containing surface structures on microorganisms

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31
Q

Mannose-binding lectin

A

Acute phase protein produced by the liver that is found in the bloodstream after an inflammtory insult

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32
Q

MBL-associated serine proteases (MASPs)

A

Part of the lectin complement pathway activation

MASPs cleave C4 and C2 - after which C4b attaches to pathogen surface and binds C2a forming the classical C3 convertase (C4b2a)

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33
Q

iC3

A

Initiates the alternative complement pathway - C3 spontaneously hydrolyzes into C3(H2O) = iC3

Rate of C3 hydrolysis is increased by LPS and other pathogen surface componenets

iC3 binds factors B and D

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34
Q

The alternative complement pathway

A
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35
Q

What induces factor B cleavage in the alternative complement pathway?

A

Binding of iC3 (C3H2O) to factors B and D -D then cleaves B

Produces Bb and Ba and yields soluble C3 convertase = C3(H2O)Bb which cleaves C3 into C3a/C3b

C3b binding to pathogen surface binds more factors B and D

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36
Q

C3bBb

A

Alternative C3 convertase

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37
Q

C3b2Bb

A

Alternative C5 convertase - cleaves C5 into a/b components to start MAC formation

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38
Q

MAC formation

A
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39
Q

What types of pathogens are C3 deficient patients susceptible to?

A

Encapsulated bacterial species (i.e. Streptococcus pneumoniae)

Becuase of C3b opsonization is important in killing encapsulated pathogens early during infection before IgG is made

Most severe form of complement deficiency

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40
Q

What type of pathogens are patients with deficiencies in MAC componenets susceptible to?

A

They are susceptible to systemic infections by bacteria in the genus Neisseria (Gram -)

These Pt’s typically present after age of ten w/ recurrent episodes of N. meningitidis infections

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41
Q

CR1

A

Expressed primarily on macrophages, neutrophils, and erythrocytes

Binds to C3b

Phagocytosis or to protect RBCs from complement by inhibiting convertase formation

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42
Q

C3a/C4a/C5a receptors

A

Expressed on mast cells, macrophages, and neutrophils (along with others)

Binding to C3a or C5a activates release of inflammatory mediators from mast cells and macrophages

Neutrophil chemotaxis toward site of complement activation

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43
Q

Major biologic functions of complement pathways

A

Cytolysis (MAC formation)

Opsonization (C3b)

Inflammation (C3a/C5a)

Immune complex removal

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44
Q

Where are immune complexes deposited if unable to be removed?

A

Within areas of high pressure - microvasculature of the kidney glomeruli, joints, and skin

45
Q

Characterize immune complex disease

A

Fever
Acute kidney injury
Skin rash
Joint swelling and pain
Clot formation

SLE - immune complexes cause these issues

46
Q

Passive regulation of complement

A

C3 and C5 convertases are unstable and active for only a short time after assembly - do not stay activated unless constantly stimulated by Ab/CRP binding, MBL binding, or present of bacterial cell wall components (i.e. LPS)

47
Q

C1 esterase

A

aka C1 inhibitor

Soluble in serum

Binds C1 and blocks classical complement cascade initiation

Only classical pathway

48
Q

Factor H/I

A

Regulates all complement pathways

Soluble in serum

Bind and cleave C3b = and all convertases that contain C3b

Most important for turning off alternative pathway in absence of paths

49
Q

Decay accellerating factor (DAF/CD55)

A

Membrane bound host cell protein

Bind C3b and blocks all C3 and C5 convertases containing C3b

Protects host cell surfaces from C3b opsonization and MAC by all pathways

50
Q

Membrane inhibitor of reactive lysis

A

MIRL/CD59

Host cell membrane bound

Binds MAC and prevents C9 polymerization

51
Q

Paroxysmal nocturnal hemoglobinuria

A

CD55/DAF or CD59/MIRL deficiency

Results from mutations in the PIGA (phosphatidylinositol glycan class A) gene and prevents addition of GPI (glycosyl phosphatidylinositol) anchors to host cell membrane-bound compliment inhibitory proteins CD55/DAF and CD59/MIRL during hematopoeisis

CD55/DAF and CD59/MIRL are no longer tethered to RBC membranes

Pt’s present w/ episodic dark-colored uring (particularly in the morning) fatigue, tachycardia, and SOB - all due to anemia and reduced O2 saturation

52
Q

Lab test to assess complement pathway function

A

CH50 and AH50 tests

CH50 - assays classical and alternative complement pathway function combined

AH50 - assays only alternative complement pathway function (Mg2+ - EGTA buffer inhibits classical pathway activation)

If deficiency is indicated - antigen-capture ELISA will be used to determine which complement factor is lacking

53
Q

Leukocyte Adhesion Deficiency Type 1

A

-Due to defective beta-2-integrins (CD18)

-Results in recurrent skin/mucosal infections without purulence

-Delayed umbilical cord separation

-Peripheral leukocytosis

May present w/ loss of adult teeth by adolescence due to periodontitis

54
Q

Chediak-Higashi Syndrome

A

Caused by a defective lysosomal trafficking regulator gene (mutated LYST gene)

Immunodeficiency - recurrent infections w/ pyrogenic bacteria (i.e. LPS secreting Gram-)

Oculocutaneous albinism

Neurologic abnormalities

Giant lysosomal granules w/i WBCs

55
Q

Chronic granulomatous disease

A

Recurrent infections by catalase-positive organisms w/ normal immunoglobins and no leukopenia:

Staphylococcus aureus
Kurkholderia cepacia
Serratia marcescens
Norcardia
Asperigullus

X-linked disorder

Results from neutrophils having and impaired respiratory burst secondary to defective NADPH oxidase

Nitroblue tetrazolium test - dx CGD and check NADPH oxidase activity

Absence of fluorescence on dihydrohodamine flow cytometry can also dx (dihydrorhodamine is normally oxidized and fluoresces green)

56
Q

Myeloperoxidase Deficiency

A

Myeloperoxidase - enzyme in cytoplasm of neutrophils that catalyzes production of hypochlorite from H2O2 and Cl-

Usually asymptomatic but may cause invasive Candida infections

Green discoloration of pus or sputum seen during common bacterial infections is due to the presence of myeloperoxidase

57
Q

Terminal complement deficiencies

A

Inability to form MAC - Pt’s susceptible to infections with Neisseria species

Evaluation will show decreased activity of the classical (CH50) complement cascade and of the alternative (AH50) cascade

58
Q

Deficiency of complement factor C3

A

Associated w/ recurrent pyogenic infections due to impaired opsonization of bacteria

59
Q

Hereditary angioedema

A

Characterized by recurrent episodes of cutaneous and mucosal swelling due to a deficiency of C1 inhibitor along with low levels of serum C4

60
Q

Deficiency of what complement factor leads to excess production of bradykinin?

A

A deficiency of C1 inhibitor

Excess production of bradykinin produces angioedema

61
Q

Histologic characterization of granulomas

A

Aggregates of activated macrophages that assume an epithelioid appearance (epithelioid macrophages)

Epithelioid macrophages may fuse together to form multinucleated cells (Langhans giant cells) surrounded by a rim of Th1 lymphocytes

62
Q

CD14

A

A monocyte marker

Stains the activated epithelioid macrophages that form granulomas

63
Q

Non-caseating granulomas

A

Lack a central area of necrosis - i.e. sarcoidosis

64
Q

Result of increased 1-alpha-hydroxylase activity in macrophages

A

Hypercalcemia - increased 1-alpha-hydroxylase activity increases vitamin D formation

65
Q

Four stages of wound healing

A
  1. Hemostasis (fibrin clot formation)
  2. Inflammation (cellular infiltration)
  3. Proliferation (reepithelization, fibroplasia, and angiogenesis)
  4. Maturation (collagen remodeling)
66
Q

Tumor necrosis factor-alpha

A

Proinflammatory cytokine secreted primarily during the inflammatory phase of wound healing

67
Q

When does the proliferation phase of wound healing occur?

A

3 days to 5 weeks after injury

Characterized by angiogenesis - stimulated by FGF and VEGF and the deposition of type III collagen

68
Q

What characterizes granulation tissue

A

Proliferating capillaries and fibroblasts

69
Q

Remodeling (maturation) stage of wound healing

A

Occurs between 3 weeks and 2 years after injury

Type I collagen is the primary collagen in mature scar tissue (also present in bones, tendons, ligaments, and skin)

Myofibroblasts and metalloproteinase secretion is important for wound contraction

70
Q

Healing by first intention

A

Involves limited granulation tissue formation (minimal scar formation and no wound contraction)

71
Q

Keloids

A

Large, irregular masses that result from excessive deposition of type I and type III collagen in dermis due to the excess production of transfroming growth factor-beta (TGF-β) by fibroblasts

More commong in African Americans - typical site being earlobes

Increased prod. of hyalinized collagen

72
Q

Histologic characterization of keloid scars

A

Abnormally broad, disorganized eosinophilic bands of collagen in the dermis

73
Q

Hypertrophic scars

A

Result from localized excess production of scar tissue (increased type III collagen) due to excess production of transforming growth factor-beta (TGF-β)

Histologically - parallel organized arrangement of collagen in dermis

74
Q

Dupuytren contracture

A

Consists of fibroblastic proliferation and thickening of the palmar fascia (palmar fibromatosis)

Characterized by inability to extend the fourth and fifth fingers

Fibrotic nodules and cords forming along the flexor tendons that limit the extension of the affected digits are pathognomonic

75
Q

Congenital torticollis

A

Unilateral fibrosis of sternocleidomastoid muscle - often caused by intrauterin malposition of the fetal head - may be associated w/ a large body (fetal macrosomia) or decreased amniotic fluid (oligohydraminios)

Contraction of the sternocleidomaastoid muscle causes head to tilt toward affected muscle - chin points away from affected muscle

76
Q

What is the most common localized form of fibroblast proliferation?

A

Dupuytren contracture

77
Q

Peyronie disease

A

Penile fibromatosis - curved penis due to localized proliferation of fibroblasts on the dorsolateral aspect

78
Q

During tissue repair, what connective tissue is deposited first?

A

Type III collagen (by fibroblasts) and then it is replaced by type I collagen

79
Q

Transforming growth factor alpha (TGF-ɑ)

A

Promotes epithelial cell proliferation, growth, and differentiation

80
Q

Transforming growth factor-beta (TGF-β)

A

Stimulates proliferation of fibroblasts and smooth muscle cells

Also decreased degradation of extracellulalar matrix by metalloproteinases in the skin following an injury

81
Q

Platelet derived growth factor (PDGF)

A

Found in alpha granules of platelets

Stimulates the proliferation of fibroblasts, smooth muscle cells, and monocytes

PDGF in excess can cause fibrosis of bone marrow (myelofibrosis)

82
Q

IL-12

A

Secreted by macrophages to induce CD4+ helpter T cells to differentiate into TH1 cells

83
Q

What cytokines are secreted by Th1 cells

A

Interfereon gamma

Interleukin-2

Proinflammatory

84
Q

Cytokines secreted by Th2 cells

A

IL-4

IL-5

IL-6

IL-10

IL-13

85
Q

What cytokine converts macrophages to epithelioid cells?

A

INF-gamma

why anti-TNF therapy can cause disseminated TB

86
Q

Basophils

A

Leukocyte with numerous deeply basophilic granules w/i cytoplasm that completely hide nucleus

Have surface receptors for IgE

Release histamine

87
Q

Basic protein

A

Secreted by eosinophils - toxic to helminthic parasites

88
Q

Arylsulfatase

A

Released by eosinophils - neutralizes leukotrienes

89
Q

What cell secretes histaminase?

A

Eosinophils

90
Q

WBCs involved in chronic inflammation

A

Often associated w/ increased numbers of monocytes and lymphocytes, but eosinophils and basophils are also types of chronic inflammatory cells

91
Q

Neutrophils with more than five nuclear lobes

A

Hypersegemented, think megaloblastic anemia

92
Q

What normally inactivates bradykinin?

A

ACE - why you cannot give ACE inhibitor (i.e. captopril) to Pt w/ C1 esterase inhibitor deficiency

Familial Angioedema

93
Q

Familial angioedema

A

Deficiency of C1 esterase inhibitor

Episodic nonpitting edema of soft tissue (esp the lips)

Severe abdominal pain and cramps - occasionally accompanied by vomiting - may be caused by edema of GI tract

C1 esterase inhibitor prevents conversion of prekallikren and kininogen to bradykinin -

Deficiency of C1 esterase inhibitor leads to excess production of bradykinin and increased vascular permeability - stimulates smooth muscle contraction, dilates blood vessels, and causes pain

ACE inhibitors contraindicated since ACE inactivates bradykinin

94
Q

CD18

A

beta-2-integrins - leukocytes adhesion and transmigration during acute inflammation

Deficiency - neutrophils won’t be found at sites of infection (no pus)

95
Q

Which is the most important cell type for initiating inflammatory responses in tissues?

A

Macrophages - resident in tissue - recruit nuetrophils

PAMPs bind PRR and induce inflammation - secrete cytokines/chemokines

96
Q

What complement pathway does LPS induce?

A

The alternative pathway

97
Q

What deficiency is indicated by recurrent Neisseria infections of the same Pt?

A

Late complement deficiency (MAC assembly - C3 and later)

98
Q

Which complement cascade pathway is responsible for clearing immune complexes once activated?

A

The classical complement pathway

Therefore, C1q/C2/C4 deficiencient patients are at increased risk for developing systemic erythematous lupus

99
Q
A

Leukocyte adhesion deficiency

Leukocyte adhesion deficiency, which is due to defective beta-2-integrins (CD18), is characterized by failure of leukocyte adhesion and migration and results in recurrent skin and mucosal infections without purulence, delayed umbilical cord separation, and peripheral leukocytosis.

100
Q
A

Mutations involving LYST

Chediak-Higashi syndrome, which is caused by a defective lysosomal trafficking regulator gene (mutated LYST gene), is characterized by immunodeficiency (recurrent infections with pyogenic bacteria), oculocutaneous albinism, neurologic abnormalities, and giant lysosomal granules within white blood cells.

101
Q
A

Defect involving NADPH oxidase

Chronic granulomatous disease, which is characterized by recurrent infections by catalase-positive organisms with normal immunoglobulins and no leukopenia, results from neutrophils having an impaired respiratory burst secondary to defective NADPH oxidase.

102
Q

Terminal complement deficiencies (C5-C9) result in inability to form the membrane attack complex, which renders affected patients more susceptible to infections with what pathogenic species.

A

Neisseria

103
Q
A

INF-gamma

Non-caseating granulomas, which lack a central area of necrosis, can be found in multiple different clinical disorders, such as sarcoidosis. Th1 cells produce IL-2 and interferon-gamma, which promote further T-cell response, activation of macrophages, and differentiation of macrophages into giant cells. INF-gamma converts macrophages to epithelioid cells, which forms granulomas, while IL-2 stimulates the autocrine proliferation of Th1 cells.

104
Q

Inheritance pattern of chronic granulomatous disease

A

X-linked recessive

105
Q

Dihidrordamine Test

A

Meaures NADPH oxidase activity - not concentration of neutrophils

Low NADPH oxidase activity - multiple granulomas and chronic infection w/ Aspergillus (Aspergillus pneumonia)

106
Q

What types of viruses does TLR3 detect?

A

All RNA viruses (even ssRNA - becomes dsRNA when it reproduces)

107
Q

Healing by secondary intention

A

Larger defects that heal w/ granulation tissue formation and possible scar contraction (mediated by myofibroblasts)

108
Q

Caseating granulomas

A

Characteristic of certain fungal infections and tuberculosis (classic infectious granulomatous disease)

MI Immuno/Heme (35 decks)

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