Immune Response and Hypersensivity

What is innate immunity?

Natural immunity

Immediate

Nonspecific

Present before exposure

Which immune system uses Toll-like receptors?

Innate immune system

Used to recognize microbial molecules and molecules of damaged cells

What is adaptive immunity?

Acquired immunity

Slower initial response

Highly specific

Develops later → Strong response

Vaccination

What are the major components of innate immunity?

Epithelial barrier (skin)

Phagocytes/Macrophages

Neutrophils

NK cells

Complement proteins (plasma proteins)

What are the major functions of innate immunity?

Cytokine production

Leukocyte recruitment

Complement activation

Inflammation

Antiviral defense through type I interferons

What are PAMPs?

Pathogen-associated molecular pattern

Microbial structures shared among organisms that help them infect/spread

What is inflammation?

Recruitment of immune cells to site of infection

What are examples of anti-viral defense?

Dendritic

NK cells

What are Toll-like receptors (TLRs)?

Receptors that bind common bacterial or viral products like LPS or dsRNA

Once activated, they stimulate NF-κB signaling and cytokine cascades

What are the two types of adaptive immunity?

Humoral immunity

Cell-mediated immunity

What makes up humoral immunity?

Extracellular defense

Bacteria

Mediated by B-cells

Production of antibody

End up as Memory cells

What happens to activated B-cells?

They differentiate into plasma cells and memory B-cells

What are the components of the adaptive immunity?

Lymphocytes (B-cells, T-cells)

Antibodies (humoral)

What is the function of NK cells?

Kill cells infected by microbes or that are stressed beyond repair

Do not need activation

What makes up the cell-mediated response?

Intracellular defense

Viral

Mediated by T-cells

Direct action on virus or virally-infected cell

End up as Effector cells

What happens to activated T-cells?

They proliferate and differentiate into helper T-cells or cytotoxic T-cells

Where do B-cells develop?

Bone marrow before migrating to blood/LNs

What is a common marker for B-cells?

CD20

What do plasma cells do?

Secrete antibodies

How do B-cells bind to antigens (foreign particles)?

Antibodies (immunoglobulins) expressed on cell surface

Where do T-cells mature?

Thymus before migrating into the blood/LNs

What is the common marker for T-cells?

CD3

What is the function of CD4+ T-cells?

Helper T-cells that coordinate immune response

What is the function of CD8+ (CTLs) T-cells?

Cytotoxic T-cells that binds and kill infected cells

How do T-cells use MHC?

T-cells must recognize antigen presented on self-MHC molecules

• “Checks and balances”

What do T-cell receptor (TCR) recognize?

Very specific antigen and “self-molecules”

What are two types of dendritic cells?

Interdigitating dendritic cells

Follicular dendritic cells

What are interdigitating dendritic cells?

Common antigen-presenting cells (APCs) to initiate T-cell response

What are follicular dendritic cells?

Common APCs in lymph nodes to initiate B-cell response

What is the function of interdigitating dendritic cells?

Ingest microbes or microbial products

Digests them into small antigens

Present them on the cell surface for T-cells to bind

Where are interdigitating dendritic cells found?

In organs with blood flow

• Liver, spleen, GI tract

What do specific macrophages do?

Phagocytosis → Kill microbes

APCs → B-cells, APCs → T-cells

Cytokine secretion to stimulate immune response

What are NK cells?

Non-specific (no TCR or Ig) cells that kill infected cells with cytotoxic molecules

Secrete cytokines (IFN-g)

What is ADCC?

Antibody-dependent cellular cytotoxicity

Cells coated with IgG can be lysed by NK cells, monocytes, and neutrophils

Can be seen in Type II hypersensivity

What are primary lymphoid organs?

Bone marrow

Thymus

What are the secondary lymphoid organs?

Lymph nodes

Spleen

MALT (tonsils, Peyer patches)

What is another name for the MHC system?

Human leukocyte antigen (HLA) system

What are MHC?

Major Histocompatibility Complex

T-cells’ major recognition molecule

• Abnormalities lead to autoimmune diseases

What cells are expressed MHC Class I?

ALL nucleated cells

• HLA-A, HLA-B, HLA-C

• Linked to B2-microglobulin

Which T-cells recognize MHC Class I?

CD8+ T-cells

What antigens are presented on MHC Class I?

Intracellular/Cytoplasmic antigens (especially viral proteins)

Which cells express MHC Class II?

Immune cells

• APCs

• B-cells

• Immune cells

NO B2-microglobulin

Which T-cells recognize MHC Class II?

CD4+ T-cells

What antigens are presented on MHC Class II?

Extracellular antigens internalized by APCs

What is a haplotype?

Combination of HLA genes in you

• One set from each parents

What are “HLA-matches” important for?

Organ transplants

• Rejection happens when NOT well matched

• Only identical twins are truly 100% matched

Which cytokines are important in innate immunity?

TNF

IL-1

IL-12

IFN-γ

Which cytokines are important in adaptive immunity?

IL-2

IL-4

IL-5

IFN-γ

What is the function of cytokines?

Initiate and regulate immune response

• Lymphocytes, dendritic cells, macrophages, others

Which cytokines are important in hematopoiesis?

GM-CSF

What is the function of TH1 cells?

Macrophage activation via IFN-γ

What is the function of TH2 cells?

B-cell activation via IL-4

What is the function of TH17 cells?

Recruit neutrophils and monocytes

What are activated by antigen proliferate?

Naive T-cells

• Migrate to site of infection

CD4+ T-cells react to IL-2 early in response

What are some CD4+ effector cells that T-cells differentiate into?

TH1 — Macrophage activation by IFN-gamma

TH2 — B-cell activation by IL-4

TH17 — Neutrophil/monocyte recruitment

Which immunoglobulin is most important in mucosal secretions?

IgA

Which immunoglobulin is the main antibody against protein antigens?

IgG

Which immunoglobulin is produced first in primary immune responses?

IgM

Which antibody crosses the placenta?

IgG

Which immunoglobulin is associated with parasites and allergies?

IgE

Which immunoglobulin stimulates eosinophils to kill parasites?

IgE

What are isotype switching?

Change function/effect of Abs

What is affinity maturation?

Small mutation that increase affinity of Ab for Ag

What are neutralizing Ab?

Prevent microbes from infecting cells

What are opsonizing Ab?

Bind and coat surface for phagocytosis

What pathway is activated by antibodies?

Classical pathway (complement activation)

What is ‘IVIg‘?

Intravenous immunoglobulin (1x/month)

What is the lifespan of memory cells?

Can live for years (vaccination!)

• Hide in tissues around body ready to respond quickly

Most cells that respond rapidly to infection undergo what?

Apoptosis after the infection has cleared

What are lymphocytes?

Mediators of adaptive immunity

The only cells with specific and diverse antigen receptors

What happens to individuals exposed to Ag?

Individuals become sensitized

• Repeat exposure can trigger excessive and injurious repsonse

What are some examples of exogenous and endogenous triggers?

Pollen, egg, peanut, chemicals

Autoimmune disease

What is often associated with hypersensitivity reaction?

Genetic susceptibility

• HLA genes (HLA B27)

What imbalance does hypersensitivity reflect?

Between the effector mechanisms and the control mechanisms

What mediates Type I hypersensitivity?

TH2 cells with:

• IgE

• Mast cells

• Eosinophils

What are examples of Type I hypersensitivity?

Allergies

Asthma

Anaphylaxis

What is released by the TH2 cells of Type I hypersensitivity?

Vasomediators and pro-inflammatory cytokines

What mediator causes increased vascular permeability and bronchoconstriction in Type I hypersensitivity?

Histamine

What are the preformed mediators of Type I Hypersensitivity?

Vasoactive amines: Histamine

Enzymes: Proteases and hydrolases

Proteoglycans: Chondroitin sulfate

What is an overview of Type I hypersensitivity?

Rapid (within minutes) immunologic reaction

Commonly called “allergies”

Can be minor (red whelp) or fatal (anaphylaxis)

Mediated by IgE activation of mast cells

What are the two phases of Type I hypersensitivity?

Rapid response — 5-30 minutes

Late phase response — 2-24 hours

What happens during the rapid response of Type I hypersensitivity?

Vasodilatation, edema and smooth muscle spasm

Mediated by preformed granule release

What happens during the late phase response of Type I hypersensitivity?

Found in 50% of patients (allergic rhinitis, asthma)

Have infiltration of tissue by monocytes, eosinophils (IL-5), neutrophils, basophils

No needed additional exposure to antigen

What leukocyte is strongly associated with late-phase allergic reactions?

Eosinophils

What causes Type II (Ab-mediated) hypersensitivity?

Abs that react with Ags present on cell surfaces or in extracellular matrix

• Intrinsic: cell membrane or matrix proteins

• Exogenous: drug metabolites

What is a Type III (immune complex) hypersensitivity?

IgG/IgM bind circulating Ags and form complexes that deposit in tissue and induce inflammation

What is a Type IV (cell-mediated) hypersensitivity?

TH1/CTLs cause cellular and tissue injury

What is the COX pathway of Type I hypersensitivity?

Phospholipase A2 → Arachidonic acid → PGE/LT3

What is the function of Leukotriene C4/D4?

Powerful vasoactive molecule

What is the function of Leukotriene B4?

Neutrophil chemotaxis

What is the function of Prostaglandin D2?

Bronchospasm and mucus secretion

What is the function of Platelet Activating Factor (PAF)?

Platelet aggregation

Histamine secretion

Vascular permeability

Vasodilation

Neutrophil/eosinophil chemotaxis

What cytokines are a part of Type I hypersensitivity?

Mast cells, which secrete:

• TNF

• IL-1

• IL-4 (TH2 response)

• Chemokines

What cytokines drive mast cell degranulation and inflammatory response in Type I hypersensitivity?

LT-C4

PAF

What is systemic anaphylaxis?

Vascular shock, widespread edema, difficulty breathing due to respiratory distress

Caused by:

• Proteins in medications (hormones, penicillin, etc)

• Food allergens (peanuts)

• Insect toxins (bee venom)

May react to very small doses but respond to EPI

What are the responses (from minor to most severe) of systemic anaphylaxis?

Itching/Hives → Contraction of respiratory bronchioles → Laryngeal edema → Vomiting/Diarrhea → Laryngeal obstruction or shock → Death

How much of the population suffers from allergies to common environmental allergens

10-20%

What makes ABs bifunctional?

One end binds Ag and neutralizes

Opposite end has Fc region that initiates effector functions

What is the main method for removing cells coated by Abs (Type II)?

Opsonization and phagocytosis

What order does Antibody-Dependent Cellular Cytotoxicity (ADCC) + Phagocytosis occur (Type II)?

Transfusion reaction

Hemolytic disease of the newborn

Autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia

Drug reactions