The Adaptive Immune Response

B-cells

The innate immune system provides immediate protection.The adaptive response takes time to develop and is antigen specific.

Activation of B and T lymphocytes

Plasma cellsNaive

Naive

ADAPTIVE IMMUNITY

The adaptive immune system consists of lymphocytes and their products, including antibodies.

The receptors of lymphocytes are much more diverse than those of the innate immune system, but lymphocytes are not inherently specific for microbes, and they are capable of recognizing a vast array of foreign substances.

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There are two types of adaptive Immunity

Humoral immunity: mediated by B lymphocytes and their secreted products, antibodies (also called immunoglobulins, Ig) that protects against extracellular microbes and their toxins.

Cellular immunity: mediated by T lymphocytes and is responsible for defense against intracellular microbes.

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Types of Adaptive Immune Reponses

Although lymphocytes appear morphologically unimpressive and similar to one another, they are actually remarkably heterogeneous and specialized in molecular properties and functions.

Lymphocytes and other cells involved in immune responses are not fixed in particular tissues (as are cells in most of the organs of the body) but are capable of migrating among lymphoid and other tissues and the vascular and lymphatic circulations.

This feature permits lymphocytes to home to any site of infection.

In lymphoid organs, different classes of lymphocytes are anatomically segregated in such a way that they interact with one another only when stimulated to do so by encounter with antigens and other stimuli.

Lymphocytes

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Mature lymphocytes that have not encountered the antigen for which they are specific are said to be naive (immunologically inexperienced).

After they are activated by recognition of antigens and other signals lymphocytes differentiate into:

effector cells, which perform the function of eliminating microbes.

memory cells, which live in a state of heightened awareness and are better able to combat the microbe in case it returns.

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B LymphocytesB lymphocytes develop from precursors in the bone marrow.

Mature B cells constitute 10% to 20% of the circulating peripheral lymphocyte population and are also present in peripheral lymphoid tissues such as lymph nodes, spleen, and mucosa-associated lymphoid tissues.

B cells recognize antigen via the B-cell antigen receptor complex.

Membrane-bound antibodies called IgM and IgD, present on the surface of all mature, naive B cells, are the antigen-binding component of the B-cell receptor complex.

Each B-cell receptor has a unique antigen specificity, derived from RAG-mediated rearrangements of Ig genes.

After stimulation by antigen and other signals, B cells develop into plasma cells that secrete antibodies, the mediators of humoral immunity.

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Immunoglobulins (cont.)• Biologic properties of immunoglobulin

domains Ch3 - cytotrophic reactions involving:

• macrophages and monocytes• heterologous mast cells• cytotoxic killer cells• B cells

Ch2 • binding complement• control of catabolic rate

Vh/Vl• antigen binding

B Lymphocytes.. 3' (DNA)α2εγ4

µ δ γ1γ3 α1

J JJV V V D D D

Germline

RearrangedV V V D D J J µ

V V V

V D J

J µ

D J J µ

1° TranscriptV D J

µ µ-mRNA

ΨγΨε

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44 Variable (V) gene segments,[2] plus 27 Diversity (D) gene segments and 6 Joining (J) gene segments.[3] The light chains also possess 2 Constant (Cμ and Cδ) gene segments and numerous V and J gene segments, but do not have D gene segments. DNA rearrangement causes one copy of each type of gene segment to go in any given lymphocyte, generating an enormous antibody repertoire; roughly 3×1011 combinations are possible, although some are removed due to self reactivity. (https://en.wikipedia.org/wiki/V(D)J_recombination)

B Lymphocytes

. GermlineDNAJ Hind III

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VDJ

B cell leukemiaµ

DJ

Allele A

AlleleBGermline Leukemia

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J probe

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In addition to membrane Ig, the B-cell antigen receptor complex contains a heterodimer of two invariant proteins called Igα and Igβ.

B cells also express several other molecules that are essential for their responses. These include complement receptors, Fc receptors, and CD40.

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Upon activation, B lymphocytes proliferate and then differentiate into plasma cells that secrete different classes of antibodies with distinct functions (Fig. 6-12).

Upon activation, B lymphocytes proliferate and then differentiate into plasma cells that secrete different classes of antibodies with distinct functions (Fig. 6-12).

Many polysaccharide and lipid antigens have multiple identical antigenic determinants (epitopes) that are able to engage many antigen receptor molecules on each B cell and initiate the process of B-cell activation.

Typical globular protein antigens are not able to bind to many antigen receptors, and the full response of B cells to protein antigens requires help from CD4+ T cells.

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B cells ingest protein antigens into vesicles, degrade them, and display peptides bound to MHC molecules for recognition by helper T cells. The helper T cells express CD40L and secrete cytokines, which work together to activate the B cells.

Immunoglobulins• IgG, IgM and IgA constitute 95% of serum

immunoglobulins• IgE trace, IgD B cell membrane associated• Monomeric IgM on B cell surface

constitutes B cell receptor• B cell antigen receptor complex contains

nonpolymorphic transmembrane proteins like the CD3 proteins of TCR, Igα and Igβ

Each plasma cell secretes antibodies that have the same antigen binding site as the cell surface antibodies (B-cell receptors) that first recognized the antigen.

Polysaccharides and lipids stimulate secretion mainly of IgM antibody.

Protein antigens, by virtue of CD40L- and cytokine-mediated helper T-cell actions, induce the production of antibodies of different classes, or isotypes (IgG, IgA, IgE).

Cytokines that induce isotype switching include IFN-γ and IL-4.

Helper T cells also stimulate the production of antibodies with high affinities for the antigen.

This process, called affinity maturation, improves the quality of the humoralimmune response.

Isotype switching and affinity maturation occur mainly in germinal centers, which are formed by proliferating B cells, especially in helper T cell-dependent responses to protein antigens.

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Signal 1 Signal 2

Helper T cells are required for efficient isotype switching, affinity maturation and generation of long lived memory B cells

Antibodies bind to microbes and prevent them from infecting cells, thus “neutralizing” the microbes. IgG antibodies coat (“opsonize”) microbes and target them for phagocytosis, since phagocytes (neutrophils and macrophages) express receptors for the Fc tails of IgG. IgG and IgM activate the complement system by the classical pathway, and complement products promote phagocytosis and destruction of microbes.

The production of most opsonizing and complement-fixing IgGantibodies is stimulated by TH1 helper cells, which respond to many bacteria and viruses; thus, the protective response to most bacteria and viruses is driven by TH1 cells.

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Some antibodies serve special roles at particular anatomic sites. IgA is secreted from mucosal epithelia and neutralizes microbes in the lumens of the respiratory and gastrointestinal tracts (and other mucosal tissues).

IgG is actively transported across the placenta and protects the newborn until the immune system becomes mature.

IgE and eosinophilscooperate to kill parasites, mainly by release of eosinophil granule contents that are toxic to the worms. TH2 cells secrete cytokines that stimulate the production of IgE and activate eosinophils, and thus the response to helminths is orchestrated by TH2 cells.

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Most circulating IgG antibodies have half-lives of about 3 weeks.

Some antibody-secreting plasma cells migrate to the bone marrow and live for years, continuing to produce low levels of antibodies.

The majority of effector lymphocytes induced by an infectious pathogen die by apoptosis after the microbe is eliminated, thus returning the immune system to its basal resting state, called homeostasis.

The initial activation of lymphocytes also generates long-lived memory cells, which may survive for years after the infection.

Memory cells are an expanded pool of antigen-specific lymphocytes (more numerous than the naive cells specific for any antigen that are present before encounter with that antigen), and that respond faster and more effectively when re-exposed to the antigen than do naive cells. This is why the generation of memory cells is an important goal of vaccination.

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