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REVISION QUESTIONS
- What are the effector cells of the innate immune system?
- Which cells are responsible for immune memory?
- In which anatomical structure are the antigens processed by lymphocytes?
Davies
B cell
T cell
Mast cell
Neutrophil
Eosinophil Antibodies
Naturalkiller cell
Dendritic cell
Granulocytes
Complement protein
γδ T cell
Natural killer T cell
Macrophage
Basophil
Innate immunity(rapid response) Adaptive immunity(slow response)
CD4T cell + CD8 + T cell
B-lymphocytes
T-lymphocytes
B-cell receptor
T-cell receptor
epitope
epitope
antigen
MHC
Tonsils and adenoids
Lymph nodes
Appendix Bone marrow
Lymph nodes Lymphatic vessels Thymus
Spleen
Peyer’s patches
Lymph nodes Lymphatic vessels
1 The immune system
The immune response
Lymphocytes develop in primary lymphoid tissue (bone marrow [BM], thymus) and circulate towards secondary lymphoid tissue (lymph nodes [LN], spleen, MALT).
The Ag reach the LN carried by lymphocytes or by dendritic cells. Lymphocytes enter the LN from blood transiting through specialised endothelial cells.
The Ag is processed within the LN by lymphocytes, macrophages, and other immune cells in order to mount a specific immune response.
The immune system comprises two arms functioning cooperatively to provide a comprehensive protective response: the innate and the adaptive immune system.
The innate immune system is primitive, does not require the presentation of an antigen, and does not lead to immunological memory. Its effector cells are neutrophils, macrophages, and mast cells, reacting within minutes to hours with the help of complement activation and cytokines (CK).
The adaptive immune response is provided by the lymphocytes, which precisely recognise unique antigens (Ag) through cell-surface receptors.
Receptors are obtained in billions of variations through cut and splicing of genes and subsequent negative selection: self-recognising lymphocytes are eradicated.
Immunological memory after an Ag encounter permits a faster and heightened state of response on a subsequent exposure.
REVISION QUESTIONS
- What are the Fab and the Fc portions of an immunoglobulin?
- What distinguishes a pre-B from a pro-B from an immature B cell?
- What is meant with the term “somatic recombination”?
The immune system
Hypervariable (CDR) regions Variable regions Constant regions
SS SS Disulphide bridge SS SS Heavy chain
Light chain
Ag binding
Fab
Fc
There are 5 classes of Ig: M, G, A, E, and D, distinguished by different heavy chains. B cells can change the class of Ig produced: class switch.
Before being capable of producing Ag-specific Ig, B cells must undergo a number of transformations, first in the BM and subsequently in the LNs.
In the rest of the cells in the body (not B cells), the genes encoding for the H and L chains of the Ig are distributed in many segments so that they cannot be expressed.
The lymphocytes developed in the BM (B cells) have as their final task the production of Ag-specific immunoglobulins (Ig), which function as antibodies (Ab).
Ig are proteins secreted by or present on the surface of B cells, assembled from identical couples of heavy (H) and light (L) chains. The highly variable N terminal regions are the Ag-binding portion (Fab fragment). The constant domains interact with the Fc receptors on the effector cells.
Immunoglobulins and B-cell development
These gene segments must be rearranged within the chromosome in the B cells so the final gene structure allows the expression of a functional protein.
The first stages of B-cell development occur in the BM, where pro-B cells first rearrange the Ig H chain gene to become a pre-B cell.
Pre-B cells continue this somatic recombination process by rearranging the L chain to become an immature B cell, expressing IgM on their surface.
m chain
a chain
g chain
IgG IgA (dimer) IgM (pentamer) IgD IgE
d chain e chain
Pro-B Pre-B B cell plasma cell
DJ VDJ VDJ VDJ
Rag H L
Immature T cell
Mature helper T cell
Mature cytotoxic T cell
Antigen
TCR
CD4+ CD8+
MHC
Antigen-presenting cell
REVISION QUESTIONS
- What is the structure of the T-cell receptor?
- How can T-helper and T-cytotoxic cells be easily distinguished?
- What is the main function of cytotoxic T cells?
The immune system
T lymphocytes arise in the BM but soon migrate to the thymus, where they mature to express the Ag-binding T-cell receptor (TCR) on their membrane.
The TCR is a dimer composed of 2 chains, usually a and β. Similar to the BCR, each one of these chains includes a variable and a constant domain.
T cells are able to recognise Ag (through their TCR) only when the Ag is bound to a major histocompatibility complex (MHC) molecule.
T cells and NK cells
Activated Th cells divide and produce a clone of effector cells, which in turn secrete CK, activating other components of the immune response.
Once activated, Tc induce apoptosis of dysfunctional cells (i.e. infected) by enzymatic or signalling processes. Natural killer (NK) cells have a similar function.
Memory T cells are produced after Ag exposure. They remain quiescent and provide an enhanced response after repeated exposure to the Ag.
After migrating to the secondary lymphoid organs, naive T cells are exposed to Ag which bind to the TCR. TCR activation induces proliferation and differentiation.
T cells mature to distinct T-helper (Th) and T-cytotoxic (Tc) populations characterised by expression of CD and CD8, respectively.
There are 2 classes of MHC molecules: class I and class II. Th recognises Ag in the context of class II MHC, whereas Tc recognises Ag bound to class I MHC.
a)
b) NK do not require MHC expression to recognise target cells
M-CFS, TNF, GM-CSF, G-CSF, IL-1, IL-6, IL-11, IL-
IL-1, IL-6, IL-8, IL-10, IL-12, IL-15, TNF-α, IFN-α, -β IL-8, TNF-α Antigen
CD
Eosinophils T-cell expansion Tc cell
Th
B cells LAK cell
NK cell Plasma cell CD4+^ T cell
Mast cell Stem cell Haematopoiesis
Macrophage
Neutrophil
TGF-β
IL-3, IL-4, IL-10, IL-13, IFN-α, -γ, TNF-β
IL-2, IFN-γ, IL-2 IL-12 (Via APC) TGF- β, IL-2,IL-4, IL-13, IL-2, IFN-γ, IL- IFN-γ
IL-3, IL- IL-4, IL- IL-6 IL-12 (via APC), IL-2, IL- IL-3, IL-4, IL-
IL-3, IL-6, IL-7, GM-CSF (^) TCR MHC II
REVISION QUESTIONS
- What are cytokines and how do they exert their function?
- What is the role of the antigen-presenting cells?
- What mechanisms are employed by antibodies to result in dysfunctional cell death?
Davies
CK are low molecular weight proteins that play a key role in the induction and regulation of the immune response.
Produced by a variety of cells, their actions are mediated through their respective receptors; they exert autocrine, paracrine, and endocrine effects. CK regulate the intensity and duration of both the innate and adaptive immune response.
Immune system activity
The various individual facets of the immune response interact in a complex fashion to result in a coordinated response.
Following a rapid response by the cells of the innate system, the cells of the adaptive immune system recognise Ag, expanding and activating effectors.
APC, present throughout the body, internalise and process Ag, displaying part of it on their surface bound to a class II MHC molecule.
This way APC carry cargos of foreign Ag to lymphoid organs, where they are recognised by Th cells which initiate the adaptive response. All aspects of the adaptive response are initiated and controlled by T cells. They recruit immunological effector mechanisms by direct contact or through CK.
Antibodies may cause direct cytotoxicity by activation of the complement cascade or by recruiting effector cells (NK, macrophages, etc.) that cause cell death.
Reduced damage to host from inflammatory response
Generation of oxidants
Direct antimicrobial activity
Immunomodulation
Antibody-dependent cell cytotoxicity
Virus and toxin neutralization
Activation of complement
Opsonisation
