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CMMB 527 > Theme 9: Immunodysfunctions > Flashcards

Theme 9: Immunodysfunctions Flashcards

1
Q

What is allergy?

A

Exaggerated humoral and cellular immune response against harmless antigens/allergens

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2
Q

What is an allergen?

A

1) Physical/chemical entity that elicits an immune response in hypersensitive individuals
2) Typically proteins/glycoproteins
3) Multivalent and non-parasitic
4) Intrinsic enzymatic properties
5) Can contain PAMPs

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3
Q

How do allergens cause an allergic reaction?

A

1) Allergic reaction is provoked by excessive re-exposure through ingestion, inhalation, etc.
2) Initially enters epithelial/mucosal tissue at very low concentrations
3) TH2 response stimulated (IL-4 produced)
4) Plasma cells secrete IgE
5) IgE binds to FcεRs on mast cells and basophils
6) Reappearance of an allergen = crosslinking of receptors to cause ADD
4) Mediators act on surrounding tissues to cause acute inflammation, low BP, coma, edema

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4
Q

What is hypersensitivity?

A

Inappropriate innate/adaptive immune response to an antigen that poses little to not threat, leading to severe local or systemic response

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5
Q

What is an immediate hypersensitivty?

A

Reactions mediated by Ab or Ab/Ag complexes

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6
Q

What are delayed-type hypersensitivites?

A

Initiated by cell-mediated responses

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7
Q

What is a type I hypersensitivity?

A

Allergies - mediated by IgE interaction with a multivalent antigen

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8
Q

What is the difference between healthy and allergic people in terms of IgE concentrations?

A

1) Circulating IgE typically in low concentrations for healthy people, only produced during parasite infection
2) Allergic/atopic people produce IgE against common environmental antigens

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9
Q

What are the effects of IgE and the phases of hypersensitivity?

A

1) Crosslinks FcεRs on innate cells to initiate ADD
2) Early response is mediated by mast cell granule release
3) Later response is mediated by recruited cells (neutrophils, eosinophils, TH2)
4) Chronic phase involves basophils and fibroblasts

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10
Q

What is released during IgE-mediated ADD?

A

Histamines, proteases, chemokines, leukotrienes and prostaglandins

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11
Q

How is IgE receptor signaling regulated?

A

Through expression of inhibitory receptors, where inhibitory receptor binding outweighs IgE receptor binding

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12
Q

What is the role of FcεRIs?

A

High-affinity receptors expressed constitutively by mast cells and basophils

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13
Q

What is the role of FcεRIIs?

A

Low-affinity receptors expressed on B cells and regulates IgE production

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14
Q

What is the role of histamines?

A

Binds to H1-H4 receptors

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15
Q

What is the role of leukotrienes and prostaglandins?

A

Increases vascular permeability and mucus secretion

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16
Q

What are the cytokines/chemokines involved in type I hypersensitivities?

A

1) IL-4 and IL-13 induce TH2 response
2) IL-5 recruits and activates eosinophils
3) TNF-α contributes to anaphylaxis
4) GM-CSF stimulates production of granulocytes

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17
Q

Several categories of type I hypersensitivity reactions exist. Why is that?

A

Depends on the route of administration, allergen concentration, and prior exposure

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18
Q

What is systemic anaphylaxis?

A

Initiated by injected or gut-absorbed allergen, which can result in death by asphyxiation

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19
Q

How is anaphylaxis treated?

A

With epinephrine

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20
Q

What are localized hypersensitivity reactions?

A

When the pathology is limited to a specific tissue or organ (like in asthma or eczema), resulting from release of mediators in the immediate exposure area

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21
Q

What factors influence type I hypersensitivity development?

A

Environment (e.g., smoking, diet) and genetic background

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22
Q

What is the hygiene hypothesis?

A

Exposure to pathogens early on life may provide a better T-cell balance such that individuals are less likely to develop hypersensitivities

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23
Q

What are some drug treatments for type I hypersensitivities?

A

1) Antihistamines
2) Leukotriene antagonists
3) Inhalation corticosteroids
4) Antibody therapy
5) Hyposensitization

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24
Q

What is inhalation corticosteroids?

A

Used to treat asthma, inhibits innate immune cell activity in airways

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25
Q

What is antibody therapy against type I hypersenstivities?

A

Anti-IgE antibodies are used to prevent IgE binding to FcεRs

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26
Q

What is hyposensitization as treatment against type I hypersensitivities?

A

Repeated exposure to allergen causes a shift in Ig response

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27
Q

What is a type II hypersensitivity?

A

Antibody-mediated destruction of cells (IgG/IgM)

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28
Q

What are the 3 mechanisms that drive type II hypersensitivity?

A

1) Opsonization to enhance phagocytosis
2) Activation of complement
3) ADCC

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29
Q

What are 3 examples of type II hypersensitivity?

A

1) ABO-Ags induced agglutination
2) Rh Ag-induced hemolysis
3) Drug-induced hemolysis

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30
Q

Explain ABO incompatibility reactions

A

1) ABO = carbohydrates on RBC surface (antigens)
2) People of different blood types have antigens against all other blood types
3) Transfusion between incompatible individuals result in immediate antibody attack against donor blood = triggering of MAC
4) Degraded RBCs can build to toxic levels

31
Q

Explain hemolytic disease of newborns

A

When maternal IgG specific to rhesus antigen crosses the placenta, fetal RBCs are destroyed via complement activation
(only a problem for mothers who are Rh-)

32
Q

What is type III hypersensitivity?

A

Mediated by immune complexes that have no been cleared effectively, causing damage through release of inflammatory and vasoactive mediators

33
Q

How do type III hypersensitivities resolve?

A

Can resolve spontaneously through clearance or can be chronic in the case of auto-antigen involvement

34
Q

What are the 2 main causes for type III hypersensitivity?

A

1) Generated through antibodies that have high affinity for and readily bind antigens in a tissue
2) Compromised phagocytic system

35
Q

What is an example of a type III hypersensitivity?

A

Arthritis (involves auto-antigen which is always present, therefore immune complexes constantly form)

36
Q

What is type IV hypersensitivity (DTH - delayed type hypersensitivity)?

A

Purely cell-mediated (T cells), hence why there is a delay, and characterized by recruitment of macrophages at the inflammation site

37
Q

What is an example of type IV hypersensitivity?

A

Poison ivy contact dermatitis

38
Q

What does type IV hypersensitivity involve?

A

1) Sensitization of T cells by an antigen (particularly TH1)
2) Effector phase induced by subsequent exposure to sensitizing antigen
3) TH1 inflammatory cytokines induce recruitment and activation of macrophages
4) Prolonged activation = granuloma formation

39
Q

What is a test used to determine if someone is DTH+?

A

Skin test, where antigen is injected into the skin and patient is checked for development of a swollen/firm lesion after a couple days

40
Q

What does a positive DTH skin test result indicate?

A

The individual has a population of sensitized TH1 cells against the antigen, but does not indicate if the infection is active or from the past

41
Q

Describe the process of poison oak contact dermatitis?

A

1) Sensitization occurs when the reactive chemical compound binds to skin proteins (due to urushiol oxidation)
2) Proteins are taken up by DCs and presented on MHC II to induce TH1 formation
3) TH1 cells return to the skin and release cytokines that activate macrophages (which release inflammatory cytokines, enzymes, and ROS)

42
Q

What is autoimmunity (type V hypersensitivity)?

A

A breach of immune tolerance

43
Q

What is antigen sequestration?

A

Some tissue-specific antigens are “hidden” from the immune cells (e.g., lens of the eye), thus tolerance against these areas has not been generated

44
Q

What is peripheral tolerance?

A

Auto-reactive lymphocytes that escape central tolerance are rendered anergic (non-responsive) or are regulated by Tregs

45
Q

What are the 2 ways that Tregs can be generated?

A

1) Naturally in the thymus (nTreg)
2) In the periphery following antigen induction (iTreg)

46
Q

What do Tregs do and through what mechanisms?

A

1) Engage with antigens on MHC II complexes with TCR (CD4+) but downregulate responses via
2) Contact-dependent CTLA-4 binding
3) Contact-independent cytokine secretion (IL-10 and TGF-β)

47
Q

What is linked/bystander suppression?

A

Where Treg interactions with an APC can suppress T cells that engage separate antigen-MHC II complexes on the APC surface

48
Q

What are regulatory CD8+ T cells?

A

1) Generated in the periphery after antigen-MHC I stimulation in the presence of TGF-β
2) Lyse and inhibit APCs
3) Regulate effector cells that bind the same antigen

49
Q

What are regulatory B cells?

A

Bregs produce IL-10 to inhibit adaptive immunity

50
Q

What are myeloid-derived suppressor cells (MDSCs)?

A

Cells that can secrete IL-10 to negatively regulate autoimmunity

51
Q

What are the 4 cells involved in peripheral tolerance?

A

1) Tregs (CD4+)
2) Regulatory CD8+ T cells
3) Regulatory B cells
4) Myeloid-derived suppressor cells (MDSCs)

52
Q

What are some examples of autoimmune disease?

A

1) Type I diabetes (targets insulin-producing beta cells in the pancreas)
2) Rheumatoid arthritis (type III hypersensitivity, due to immune complex formation)
3) Systemic autoimmunity due to FoxP3 deficiency (lack of Tregs)

53
Q

What are the 5 types of primary immunodeficiencies?

A

1) Humoral deficiency
2) Complement deficiency
3) Phagocytic deficiency
4) Combined deficiency
5) Cellular (T cell) deficiency

54
Q

What are 3 examples of combined deficiency?

A

1) SCID
2) Bare-lymphocyte syndrome (no MHC II)
3) MHC I deficiency (no TAP)

55
Q

What is SCID?

A

Lack of functional T cells which also manifests as the absence of T-cell dependent B cell responses

56
Q

What can SCID be caused by?

A

1) Defective differentiation of myeloid and lymphoid lineages
2) Defective cytokine signaling in T-cell progenitors
3) Defects in purine metabolism
4) Defects in RAG1/2
5) Signaling defects of pre-TCR or TCR
6) Essentially defects in stem cells or early T-cell development

57
Q

What is bare lymphocyte syndrome?

A

Lack of MHC II molecules which results in lack of positive selection of CD4+ T cells and impaired peripheral T-helper responses

58
Q

What is MHC I deficiency?

A

Due to lack of TAP molecules, resulting in impaired positive selection of CD8+ T cells (higher susceptibility to viral infections)

59
Q

What are B cell immunodeficiencies?

A

Defined by depressed production of 1 or more antibody isotypes, usually resulting in recurring infection

60
Q

What are examples of B cell immunodeficiencies?

A

1) X-linked agammaglobulinemia
2) Selective IgA deficiency
3) X-linked Hyper-IgM syndrome

61
Q

What is X-linked agammaglobulinemia?

A

Low levels of IgG and absence of other isotypes due to defects in tyrosine kinase required for BCR signaling (B cells remain immature)

62
Q

What is selective IgA deficiency?

A

IgA-secreting B cells are unable to differentiate into plasma cells, increasing susceptibility to respiratory/GI tract infections

63
Q

What is X-linked Hyper-IgM syndrome?

A

1) Deficiency in CD40L on T cells (lack of costimulatory interactions between B cells and T cells) which limits production of antibodies for most B cells
2) Some B cells are activated by lipopolysaccharide recognition without requiring T cell help but only produce IgM

64
Q

What are some innate immunity deficiencies?

A

1) Leukocyte adhesion deficiency (limits recruitment to inflamed areas)
2) Complement deficiencies (inability to phagocytose, clear immune complexes, etc.)
3) NKC deficiencies (susceptible to viral infections and cancer)
4) Myeloid cell deficiencies (depleted phagocytic activity)

65
Q

What can NKC deficiencies be caused by?

A

1) Genetic defects that affects synapse formation
2) Interference with lymphoid lineage development or NK development

66
Q

What are examples of secondary immunodeficiencies?

A

1) Acquired hypogammaglobulinemia
2) Agent-induced immunodeficiency (irradiation, chemotherapy for cancer)
3) HIV-AIDS

67
Q

How does the HIV infection cycle work?

A

1) HIV is taken up by DCs which pass the virus onto CD4+ T cells
2) Virus is then transported to draining lymph nodes where other cells can be infected

68
Q

What is cell tropism?

A

Ability of a virus to infect specific types of cells

69
Q

What is HIV tropism determined by?

A

Which coreceptor is recognized by gp120

70
Q

What coreceptor do HIV macrophage-tropic strains use?

A

CCR5

71
Q

What do HIV T-tropic strains use?

A

CXCR4

72
Q

What are the phases of HIV-1 infection?

A

1) Acute phase where there is a spike in HIV levels, eventually controlled by antibody production
2) Asymptomatic phase where there is a gradual decrease in CD4+ T cells and increase in viral load
3) AIDS where there is a crash in CD4+ T cell numbers, allowing for high levels of HIV and opportunistic infections

73
Q

How is HIV-1 treated?

A

HAART = highly active antiretroviral therapy

CMMB 527 (10 decks)

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