Immunology Test 3

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99 Terms

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Follicular Dendritic Cells (FDCs)

  • have long processes that have complement receptors and Fc receptors

  • Capture intact

  • Antibody/Antigen/complement complexes for presentation to B-cells

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Subcapsular Sinus Macrophages

  • poorly phagocytic

  • present intact antigens on complement receptors

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3 Signals B-2 cells require to become activated

  1. binding of B-cell receptor to an antigen

    • dimerization of receptors sends activating signals

  2. binding of B cell co-receptor to complement factor C3d

    • CR1 cleaves C3b on pathogen surface to iC3b and C3d

    • CR2 binds C3d

    • CD19 enhances signaling

  3. Linked antigen recognition by Tfh cell

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T cell provides CD40L (binds B cell CD40)

  • causes B-cell to proliferate (i.e., divide to produce many B-cell copies)

  • promotes class switching and somatic hypermutation in the germinal center

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T cell provides cytokines

required for initial B-cell proliferation, cytokines determine antibody class during class switching

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When a B-cell receptor binds antigen,

it internalizes the antigen, breaks the proteins into peptide fragments, and presents peptides on MHC class II molecules

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The requirement for T-cell help

serves as a mechanism of B-cell negative selection

  • if a B-cell receptor binds self-antigen, there is unlikely to be a conjugate (partner) T-cell present

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B cell forms a conjugate pair with a Tfh cell that recognizes a linked peptide

  • CD40L and cytokines from the T cell drive B cell proliferation

  • signals are delivered through a synapse

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Activated B-cells differentiate into plasma cells in 2 waves

  • first, the B-cell-T-cell conjugate pair moves to the medullary cords to form a primary focus

    • some B-cells differentiate to plasma cells secreting low affinity IgM antibody

  • second, remaining B-cells move back to the lymphoid follicles to form a germinal center

    • germinal center B-cells undergo somatic hypermutation and class switching

    • results in high affinity, class switched antibodies

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Dark zone of Germinal centers

  • contains centroblasts

    • proliferating B-cells undergoing somatic hypermutation

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Light Zone of Germinal Centers

  • contains centrocytes sampling antigen presented by FDCs

    • centrocytes display the mutated B-cell receptor to see if it can bind antigen presented by FDCs

    • B-cells with the highest affinity receptors will bind and continue to receive survival signals from Tfh cells

    • selection occurs in increments (i.e., B-cells undergo multiple rounds of somatic hypermutation)

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Following somatic hypermutation, B-cells with a low affinity receptor

undergo apoptosis

  • cannot compete for the limited antigen presented by FDCs

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Following somatic hypermutation, B-cells with a high affinity receptor

are signaled to survive

  • the receptor binds antigen, and the B-cell continues to receive the CD40L and cytokines from a Tfh cell

  • over time, B-cell undergoes affinity maturation

    • receptor affinity (i.e., binding strength) for antigen increases over time

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Class Switching

  • largely determined by cytokines

  • takes place in germinal center

  • requires interactions between CD40 (B cell) and CD40L (T cell)

    • individuals that lack CD40L have hyper IgM syndrome

    • T-cell types other than Tfh cells can also produce cytokines that influence this

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B-cell responses to thymus-independent antigens

do not require T-cell help

  • many common bacterial antigens are TI antigens

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Two types of thymus-independent antigens

  • TI-1 antigens

  • TI-2 antigens

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At low concentration, T-1 antigens

cause antigen specific B-cell responses

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At high concentration, TI-1 antigens

cause polyclonal B-cell activation

  • cause activation of most B cell through PRRs independent of B-cell receptor specificity

  • examples: LPS and bacterial DNA which activate TLRs expressed by B cells

  • gets an initial supply of antibody in circulation while the body waits for the slower thymus-depended response to become activated

  • some of the resulting antibodies will bind to other antigens on the pathogen

  • many of the resulting antibodies will be no use

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TI-2 antigen responses

highly repetitive structures such as capsular polysaccharides

  • the antigen cross-links many receptors to send a strong activating signal

  • provides a quick antibody response to encapsulated bacteria as it can be difficult to get B-2 cells activated without an initial thymus independent response

  • responses are made primarily by B-1 cells and marginal zone B cells of the spleen

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IgM

  • first antibody class to be produced during an immune response

  • has relatively low affinity for antigen as it is produced prior to somatic hypermutation

  • forms pentamers to increase overall binding strength

  • other antibody classes are produced through class switching in the germinal center and have a higher affinity antigen binding site

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IgG

most abundant antibody in blood serum

  • 4 different subclasses with distinct functions make a good all-around antibody

  • transported across the placenta

  • after birth, maternal IgG declines during the first 6 months

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IgG, monomeric IgA and IgM

protect extravascular tissues

  • IgG and IgA are smaller than IgM and diffuse more easily into tissues

  • IgG is the most abundant class in the blood

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Dimeric IgA

protects mucosal surfaces

  • most abundant antibody class in the body

  • mucosal surfaces are expansive, and most pathogens enter through mucosal surfaces

  • transferred through breast milk to an infant to protect the infant’s mucosal surfaces

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IgE

  • binds to mast cells underlying surface and surrounding blood vessels

  • binds to Fcε receptors on mast cells and awaits antigen binding

  • when on mast cells binds antigen, the mast cell secretes inflammatory mediators

    • promote bodily functions that aim to flush out the parasite, e.g., vomiting diarrhea, increased mucus production

    • recruit other cells

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Infants

start to make their own IgM before birth and IgG and IgA at around 3 months

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High affinity neutralizing antibodies

prevent attachment of microbes, toxins, and venoms to cell surface (and therefore, prevent entry into cells)

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Monomeric IgA

can also activate the classical complement pathway, but dimeric IgA does not

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IgM and IgG activate the classical complement pathway

bind to the pathogen surface and recruit C1, which activates the classical complement pathway

  • they do not interact with C1 when not bound to the pathogen surface

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Parasites

are too large to injest

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Binding of an eosinophil

to an IgE coated parasite triggers exocytosis of granules

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Natural Killer (NK) cells

  • have a receptor for IgG

  • recognize host cells coated with IgG

    • kills infected cells

    • complements the function of CD8 T cells

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IgG antibody functions

  • most abundant class in the blood

  • protects extravascular tissues and is transferred across the placenta

  • good all-around antibody class

    • opsonization, neutralization, activation of classical complement pathway, ADCC

    • doesn’t play a major role in defense against parasites

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IgA Antibody Functions

  • most abundant antibody class in the body; dimeric IgA is the primary class that protects mucosal surfaces

  • overall, its primary function is neutralization

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IgE

defense against helminth parasites— works with mast cells, eosinophils and basophils

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IgM Antibody Functions

  • first antibody class to be secreted

  • relatively low affinity binding site and functions as a bulky pentamer

  • effective at activating the classical complement pathway

  • contributes to neutralization and protection of mucosal surfaces

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IgD Antibody Function

binds to basophils in the respiratory tract and functions in defense against respiratory pathogens

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X-linked agammaglobulinemia (XLA)

  • affects ~1 in 200,000

  • defective B cell receptor signaling during B-cell development results in no functional B-2 cells

  • role of B cells: produce antibodies

  • symptoms: susceptible to infections with extracellular bacteria and fungi, and some viruses recurrent infections can lead to tissue and organ damage

  • treatments: antibodies to treat infections

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Dendritic Cells

  • obtain peripheral tissue antigens at the infection site and travel in the lymphatics to the draining lymph node

  • present antigen to T-cells in the T-cell areas of secondary lymphoid tissues

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Inflammation

increases drainage of fluid into lymphatic vessels

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Naïve T-cells

have not yet encountered their antigen

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Effector T-cells

  • T-cells that have been activated and can carry out their function

  • if a naïve T-cell receptor binds the antigen/MHC complex presented by a dendritic cell, it becomes activated to produce this

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Secondary Lymphoid Tissues

are linked through lymphatic vessels

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T-cells

can move from tissue-to-tissue sampling antigen presented by dendritic cells

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During an infection,

antigen specific T-cells are trapped in the draining secondary lymphoid tissue very efficiently (within a couple of days)

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Immature dendritic cells

  • constantly sample antigens of all kinds in the environment

  • they become mature (activated) when:

    • a pathogen PAMP binds to a dendritic cell PRR

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Following activation, dendritic cells

  • synthesize the co-stimulatory molecule B7

  • increase antigen processing and presentation on MHC molecules

  • upregulate the chemokine receptor CCR7 (binds chemokines produced by secondary lymphoid tissues)

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T-cell Signal 1

the T-cell receptor complex (including CD4 or CD8) binds to peptide: MHC complex presented by dendritic cell

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T-cell Signal 2

CD28 on T-cell binds to the costimulatory molecule B7 on mature dendritic cell

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T-cell differentiation and proliferation

requires a third signal

  • cytokines

    • IL-2 for proliferation

    • differentiation to one of the CD4 T-cell subsets is determined by cytokines

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Dendritic cells that present a self-peptide

are not typically mature, so they do not express the co-stimulatory B7 molecule and therefore do not activate T-cells (this provides a mechanism of negative selection in the periphery)

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CD8 T-cells

often have a higher threshold for activation

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For some intracellular pathogens,

activation of the T-cell receptor and CD28 co-stimulatory receptor is sufficient to activate the T-cell.

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For many intracellular infections,

CD8 T-cells require additional help from a CD4 T-cells activated by the same pathogen.

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Effector CD8 T cells

  • T-cells form a conjugate (cognate) pair with their target cell

  • cytokines and cytotoxins are delivered through a synapse

    • focuses delivery at site of contact

  • the molecule perforin produces a pore in the target cell membrane

  • granzymes (proteases) are delivered through the pore and activate apoptosis

    • target cell undergoes apoptosis

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Following activation, a naïve CD4 T cell

differentiates into one of several subsets depending on the cytokines it receives

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ILC2 cells

act during the innate immune response and promote the type 2 response

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ILC1 cells

act during the innate immune response and promote the type 1 response

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ILC3 cells

act during the innate immune response and promote the type 3 response

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Effector CD8 T cells (cytotoxic T cells)

destroy cells infected with an intracellular pathogen

  • an infected cell will display pathogen antigens on MHC class I molecules

  • cytotoxic T-cells will kill any cells that display the same antigen that activated the T-cell

  • the T-cell no longer requires a co-stimulatory signal after it has been activated

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CD4 T-cell differentiation

is determined by the cytokines it receives at the time of activation

  • different CD4 T-cell subsets are defined by the different cytokines they produce

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Linked Recognition

the B-cell and T-cell receptors recognize different epitopes within the same antigen

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Tfh cells activate

naïve B cells and are required for the formation of germinal centers

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Activation of naïve B-cells

requires binding of CD40 to CD40L and cytokines

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T-helper 1 cells

  • help combat intracellular infections

  • upregulate mactophages (i.e., increase killing ability via phagocytosis)

    • increase ability of macrophages to destroy the material in their intracellular vesicles

    • important in the response to intracellular bacteria and viruses

  • this and macrophage form a conjugate pair

  • macrophages require 2 signals for upregulation

    • cytokine IFN-γ

    • CD40L, which binds CD40 on the macrophages

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The granuloma

is a chronic interaction between macrophages and T-cells which walls off the pathogen and prevents dissemination through the body

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T helper 2 cells

  • enhance response to helminths (worms) by eosinophils and basophil, mast cells, and IgE

  • promote bodily functions aimed to flush out the parasite

    • increased mucus production, diarrhea, vomiting, smooth muscle contraction, etc.

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T helper 17 cells

  • enhance the response to extracellular bacteria and fungi by:

    • promoting the production and recruitment of additional neutrophils

    • stimulating mucosal epithelial (barrier) cells to increase the rate of turnover and production of antimicrobial molecules (inhibits colonization of mucosal surfaces)

  • discovered in 2007

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Natural T-regulatory cells

  • produced in the thymus during T-cell development

  • some T-cells that are negatively selected become Tregs

  • recap: play important role in inhibiting the activation of potentially self-reactive T-cells

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Induced (or adaptive) Tregs

  • differentiate from naïve CD4 T-cells upon activation in the presence of anti-inflammatory cytokines

  • mainly produced in the mucosal immune system in response to harmless antigens (e.g., non-microbial antigens or antigens from commensal microbes)

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γ:δ T-cells

  • maintain tissue integrity

    • recognize conserved antigens that diminish stressed cells from healthy cells

    • kill infected/damaged cells and promote tissue repair

    • account for most T cells in tissues

  • do not interact with MHC molecules

    • do not need the CD4/CD8 co-receptors

  • can be thought of as innate-like cells

    • respond quickly to stress/infections like an innate response

    • show less receptor diversity than α:β cells

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Severe combined immunodeficiency (SCID)

  • affects 1 in 100,000

  • also known as “bubble boy disease”

  • no functional T-cells

  • several causes: IL-2R mutation, RAG protein mutation, abnormal thymic development

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Mucosal Surfaces

  • protect the gastrointestinal tract, respiratory tract, urogenital tract, and glands

  • thin, permeable, expansive

  • most pathogens enter the body here

  • are populated by commensal microbes

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Mucus

composed of mucins

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Mucins

  • glycosylated polypeptides that are cross-linked to form large, extended molecules

  • lubricates mucosal surfaces

  • protects mucosal surfaces

    • physically impedes microorganisms

    • retains antibody and anti-microbial molecules

    • turns-over every couple of days

  • produced by goblet cells in the mucosal epithelium

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Secondary Lymphoid tissues of the small intestine

include the GALT (Peyer’s pathches, isolated lymphoid follicles and appendix) and mesenteric LNs

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Microfold Cells (M cells)

transport microbial antigens from gut lumen to underlying lymphoid tissue

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Paneth cells

in the epithelium secrete antimicrobial substances

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Non-mucosal tissues

  • only have occasional contact with microbes

    • an immune response is only generated in the presence of an infection, i.e., not proactive

    • when the barrier is breached, tissue macrophages produce an inflammatory response to attract more leukocytes to the area to clear the infection

    • inflammation also causes damage to host tissues

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Mucosal tissues

  • have continuous contact with microbes

    • mucosal immune system proactively makes adaptive immune responses against antigens in the gut lumen, so it is prepared for a breach in the barrier

    • mucosal immune responses to innocuous antigens are non-inflammatory

    • if barrier is breached, infection can be cleared quickly with minimal inflammation

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Mucosal tissue macrophages

  • perform phagocytosis, but do not produce an inflammatory response

  • don’t perform inflammatory functions associated with systemic tissue macrophages

    • monocytes lose their inflammatory potential when they arrive in the lamina propria from blood

    • do not secrete inflammatory cytokines

    • do not express T cell co-stimulatory molecules in order to become activated

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Gut dendritic cells

  • promote tolerance to food antigens (no adaptive immune response)

  • move to mesenteric lymph nodes and active Tregs

    • they present antigen and secrete anti-inflammatory cytokines, which promotes differentiation of T-cells to the Treg subset

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Oral Tolerance

  • tolerance of non-microbial protein antigens taken in through the oral route

  • systemic and mucosal immune systems become unresponsive

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Mucosal dendritic cells in the secondary lymphoid tissue

  • promote an anti-inflammatory adaptive immune response

    • not the same as oral tolerance to food antigens

    • proactive, anti-inflammatory immune response

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The anti-inflammatory response involves:

  • activation of B cells to produce plasma cells secreting IgA

  • activation of Tregs (keep other T cells in check)

  • activation of some inflammatory T cell subsets (kept in check by the Tregs)

    • they are already ready and waiting if the barrier is breached

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Dimeric IgA

  • the primary antibody class that protects mucosal surfaces

  • the primary function is neutralization (a non-inflammatory function)

    • inflammatory immune cells and molecules are not present in the lumen of the gut

  • IgM contributes to the protection of the mucosal surfaces (but it is a lower affinity antibody)

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Antigen presentation by dendritic cells

can be anti-inflammatory or inflammatory depending on the cytokines present in the environment

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In the absence of a barrier breach

dendritic cells promote an anti-inflammatory response to microbial antigens

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Anti-inflammatory cytokines in the microenvironment

promote Treg differentiation and IgA production for a pro-active, anti-inflammatory response

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Breach of the barrier

by a pathogen or opportunistic commensal results in an inflammatory response

  • Tregs take off the brakes and allow inflammatory subsets to function to produce inflammatory immune response

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Comprised epithelial cells

secrete inflammatory cytokines

  • produces an inflammatory cytokine environment in the underlying tissue

  • if a pro-active immune response has already been generated, the infection may be dealt with promptly with minimal inflammation

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Celiac Disease

pro-inflammatory responses are generated against gluten

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Crohn’s Disease

pro-inflammatory responses against commensal bacteria

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After primary infection is cleared

  • relatively high antibody levels are sustained for a couple of months

  • low level of antibody is maintained in circulation indefinitely by long-lived plasma cells

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Memory Response (secondary adaptive immune response)

  • the immune response against second and subsequent exposure to an antigen

  • quicker and more effective (often clearing infection without symptoms)

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Characteristic of memory B cell response

  • protective memory is provided by low-level antigen specific antibody produced by long-lived plasma cells

  • reactive memory is provided by memory B cells

  • more antigen specific when compared to the initial number of antigen specific naïve cells

  • memory B cells have already undergone class switching and somatic hypermutation

    • they are activated earlier because it takes less antigen

    • they immediately produce class-switched high affinity antibodies

  • memory B cells are preferentially activated over new naïve B cells that would produce a lower affinity antibody

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With subsequent exposure to antigen:

  • antibody concentration increases

    • more memory cells in secondary response compared to naïve cells in primary response

    • memory cells activated quicker than naïve cells

  • the affinity of antibody for antigen continues to rise

    • memory B cells undergo further somatic hypermutation and affinity maturation

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Memory T cell characteristics

  • effector memory T cells circulate in peripheral tissues and are already differentiated and ready to act (provide protective memory)

  • central memory T cells circulate in secondary lymphoid tissues

    • undifferentiated, but more readily activated then naïve T cells (less dependent on co-stimuation

    • start producing cytokines earlier than newly activated naïve T cells (within 12-24 hrs)

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Primary Response

  • small number of pathogen-specific cells respond at the start

  • delay before pathogen-specific antibodies are produced

  • non-isotype-switched antibody having a mixture of affinities for the pathogen is produced at the start

  • high threshold of activation

  • delay before effector T cells are generated and are able to enter infected tissues

  • innate immunity works alone until an adaptive response is generated

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Secondary Response

  • large number of pathogen-specific cells respond immediately

  • pathogen-specific antibodies already present

  • antibodies are isotype-switched and have high affinity for the pathogen

  • lower threshold of activation

  • effector T cells are present and can enter infected tissue immediately

  • close cooperation between innate and adaptive immunity from the start