Lecture 10 Immune System & its Diseases I

Dr. Nabila Hamdi

MD, PhD

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ILOs • Distinguish between innate and adaptive immunity.

• Recall the cells involved in the immune response and define their roles.

• Compare and contrast the origin, maturation process, and general function of B and T lymphocytes.

• Name several antigen-presenting cells and describe their roles in adaptive defenses.

• Understand the mechanisms and key players of humoral immunity.

• Define cellular immunity and describe the process of activation.

• Describe the roles of different types of T cells and their functions in the body.

• Discuss the possible mechanisms of graft rejection and the role of MHC molecules.

• Compare and contrast the types and subtypes of hypersensitivity disorders in terms of examples, pathogenesis, clinical features, key players, antigens…

• Define self-tolerance, and describe its development in B and T lymphocytes.

• Give examples of immune deficiency diseases and differentiate between primary and secondary immune deficiencies.

• Understand the pathogenesis of HIV infection and rheumatoid arthritis.

• Cite examples of autoimmune diseases and understand their mechanisms.

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Outline 1. Overview • Definitions • Innate & Adaptive Immunity 2. Types of Immunity • Humoral Immunity • Cellular Immunity 3. Cells of the Immune System • T Lymphocytes • B Lymphocytes • Macrophages • Dendritic Cells • Antigen-presenting cells • Natural Killer Cells 4. Histocompatibility Molecules

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Overview

Immune system deficient!!

Life-threatening

Immune system harmful!!

• Hypersensitivity reactions • Graft rejection • Autoimmunity

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• Immunity refers to protection against infections.

• Immune system is the collection of cells and molecules that are responsible for defending us against the countless pathogenic microbes in our environment.

Innate & Adaptive Immunity

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Innate & Adaptive Immunity

The major components of innate immunity

Innate Immunity

• Skin • GIT • Respiratory tract

• Macrpophages • Neutrophils

Natural killer (NK) cell Complement system

Epithelia Phagocytic leukocytes

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Innate & Adaptive Immunity

Adaptive immunity is normally silent and responds (or "adapts") to the presence of infectious microbes by becoming active, expanding, and generating potent mechanisms for neutralizing and eliminating the

microbes

By convention, the terms "immune system" and "immune response" refer to adaptive (acquired) immunity.

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Types of Immunity

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Types of Immunity

Mediated by soluble antibody proteins that are produced by B lymphocytes (also called B cells)

Antibodies provide protection against intact extracellular microbes in the blood, mucosal secretions, and tissues.

Kills microorganisms by the following mechanisms:

• Direct neutralization by antibodies

• Activating complement

• Activating effector phagocytic cells (neutrophils and macrophages)

Humoral Immunity

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Types of Immunity

Mediated by T lymphocytes (also called T cells)

T Lymphocytes are important in defense against intracellular microbes.

T lymphocytes recognize antigens that have been processed (proteolytically fragmented) and presented by other cells (APCs)

Helper T cells produce cytokines to orchestrate the antimicrobial immune response of effector cells (macrophages and cytotoxic T cells).

Cytotoxic T cells directly lyse targets.

Cellular Immunity

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Cells of the Immune System

http://www.austincc.edu/apreview/PhysText/Immuno.html 11

T Lymphocytes

T lymphocytes are so called because they mature in the thymus.

T cells constitute 60% to 70% of the lymphocytes in peripheral blood and are the major lymphocyte population in spleen and lymph nodes.

By forcing T cells to see MHC-bound peptides, the system ensures that T cells can recognize antigens in other cells and thus perform their function of killing infected cells or activating phagocytes or B lymphocytes that have ingested protein antigens.

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T Lymphocytes

T cells do not detect free or circulating antigens T cells only recognize antigens associated with MHC molecules on cell surfaces

bound to proteins of the major histocompatibility complex (MHC)

http://www.austincc.edu/apreview/PhysText/Immuno.html

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T Lymphocytes

• Each T lymphocyte expresses receptors (TCR) for a single antigen

• CD4 and CD8 are expressed on distinct T-cell subsets and serve as co-receptors for T-cell activation

http://molbiol4masters.masters.grkraj.org/html/Cell_And_Molecular_Immunology5-T_And_B_Cell_Activation_And_Immunity.htm

CD4 is expressed on approximately 60% of mature T cells, whereas CD8 is expressed on about 30% of T cells; in normal healthy individuals, the CD4/CD8 ratio is about 2 : 1.

CD4 are expressed on T helper cells

CD8 are expressed on T cytotoxic cells

CD4+ cells

CD8+ cells

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T Lymphocytes CD4+ T cells are "helper" T cells because they secrete soluble molecules (cytokines) that help B cells to produce antibodies and also help effector cells to destroy microbes.

The central role of CD4+ helper cells in immunity is highlighted by the severe compromise that results from the destruction of this subset by HIV infection.

http://www.austincc.edu/apreview/PhysText/Immuno.html

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T Lymphocytes

CD8+ T cells can also secrete cytokines, but they play a more important role in directly killing virus-infected or tumor cells, and hence are called "cytotoxic" T

lymphocytes (CTLs).

http://www.austincc.edu/apreview/PhysText/Immuno.html

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MHC Molecules

• They are the “Peptide Display System of Adaptive Immunity”.

• The major histocompatibility complex (MHC) or in humans, human leukocyte antigen (HLA) complex, was discovered on the basis of studies of graft rejection or acceptance.

• The HLA complex, consists of a cluster of genes on chromosome 6.

• The HLA system is highly polymorphic; that is, there are several alternative forms (alleles) of a gene at each locus (1100 different HLA-B alleles have been described).

• Such diversity provides a system whereby a vast array of peptides can be displayed by MHC molecules for recognition by T cells.

• This polymorphism also constitutes a formidable barrier to organ transplantation.

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MHC Molecules

• Class II MHC molecules are encoded by

genes in the HLA-D region, which contains at least three subregions: DP, DQ, and DR

• They bind to peptides derived from

proteins synthesized outside the cell (e.g., those derived from extracellular bacteria).

• They are expressed mainly on dendritic

cells, macrophages, and B cells (APCs)

• Class I MHC molecules are encoded by

three closely linked loci, designated HLA-A, HLA-B, and HLA-C

• They bind to peptides derived from

proteins synthesized within the cell (e.g., viral antigens)

• They are present on all nucleated cells

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MHC Molecules

• Every individual inherits one HLA allele from each parent and thus typically expresses two different molecules for every locus.

• Different MHC alleles bind to different peptide fragments depending on the particular amino acid sequence of a given peptide.

• The inheritance of particular alleles influences both protective and harmful immune responses (good responsiveness to a viral antigen or allergic reaction )

• Many diseases are associated with particular HLA alleles (inflammatory, autoimmune)

Clinical Significance

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MHC Molecules

Each individual expresses a unique MHC antigenic profile on his or her cells ( a virtually infinite number of combinations of HLA molecules exist).

Grafts from any person will evoke immune responses in any other person and be rejected (except for identical twins).

HLA molecules of the graft evoke both humoral and cell-mediated responses, eventually leading to graft destruction.

This ability of MHC molecules to trigger immune responses is the reason these molecules are often called "antigens.“

The severity of the rejection reaction is related to the degree of donor and recipient HLA disparity. Thus, HLA typing is of clinical significance in the selection of donor-recipient combinations

Graft Rejection

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B Lymphocytes

Bone marrow-derived, or B, lymphocytes comprise 10% to 20% of the circulating peripheral lymphocyte population.

They are also present in bone marrow and peripheral lymphoid tissues (lymph nodes, spleen, tonsils, and other mucosal tissues (GIT)).

B cells can recognize and respond to the native form of many chemical structures, including proteins, lipids, polysaccharides, nucleic acids, and small chemicals.

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B Lymphocytes

B cells are the only cell lineage that synthesize antibodies, also called immunoglobulins (Ig).

After stimulation, B cells differentiate into plasma cells, which secrete large amounts of antibodies, the mediators of humoral immunity.

There are five classes, or isotypes, of immunoglobulins: • IgG, IgM, and IgA constitute more than 95% of circulating antibodies.

• IgA is the major isotype in mucosal secretions.

• IgE is present in the circulation at very low concentrations and is also found attached to the surfaces of tissue mast cells (parasitic infections & allergies)

• IgD is expressed on the surfaces of B cells but is not secreted.

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B Lymphocytes

http://www.arthritis.co.za/immunologyupdate.html

B cells recognize antigen via monomeric membrane-bound antibody of the immunoglobulin M (IgM) class, associated with signaling molecules to form the B-

cell receptor (BCR) complex

As with TCRs, each antibody has a unique antigen specificity.

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B Lymphocytes

B Lymphocytes

http://www.austincc.edu/apreview/PhysText/Immuno.html

B cells act as antigen-presenting cells: they present peptides to helper T cells and receive signals that stimulate antibody

responses to protein antigens

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Macrophages

Macrophages are chronic inflammatory cells. Macrophages act as APCs: • They express class II MHC • They ingest microbes and other particulate antigens and

display peptides for recognition by T lymphocytes

Macrophages produce cytokines (important effector cells in certain types of cell-mediated immunity)

Macrophages phagocytose microbes coated by antibody and/or complement (important effector elements of humoral immunity)

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Dendritic Cells

Cells with dendritic morphology (fine dendritic cytoplasmic processes), occur as two functionally distinct types:

Interdigitating DCs: (or more simply, DCs), • widely distributed (lymphoid & nonlymphoid tissues) • nonphagocytic cells • express high levels of class II MHC and T-cell costimulatory molecules. • The most potent APCs

Follicular DCs: • located in the spleen and lymph nodes • bear receptors for the Fc tails of IgG and for complement proteins,

and hence efficiently trap antigen bound to antibodies and complement (maintain immunologic memory) 27

Antigen-Presenting Cells

APCs are specialized to capture microbial antigens and display these to lymphocytes.

Dendritic cells are the major cells for displaying protein antigens to naive T cells to initiate immune responses.

Macrophages ingest microbes and other particulate antigens and display peptides for recognition by T lymphocytes

B cells present peptides to helper T cells and receive signals that stimulate antibody responses to protein antigens.

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Natural Killer Cells

https://gcps.desire2learn.com/d2l/lor/viewer/viewFile.d2lfile/15539/4628/mobile_pages/index.html

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Natural Killer Cells

Natural killer (NK) cells are lymphocytes that arise from the common lymphoid progenitor that gives rise to T and B lymphocytes.

Comprise 10% to 15% of peripheral blood lymphocytes.

NK cells use a limited set of activating receptors to recognize

molecules expressed on tumor or infected cells or cells with DNA damage, and then kill these cells.

To avoid attacking normal host cells, NK cells express inhibitory receptors (KIR) that recognize self class I MHC molecules, which are expressed on all healthy cells; engagement of these inhibitory receptors typically overrides the activating receptors and thus prevents activation of the NK cells

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Natural Killer Cells

French and Yokoyama Arthritis Res Ther 2004 6:8-14

Recognizes molecules expressed on tumor or infected cells

Recognizes self class I MHC molecules, which are expressed on all healthy nucleated cells

(no lysis)

Viral infections and neoplastic transformations are associated with loss of expression of

class I MHC molecules

NK cells are released from their inhibition and respond to the activating ligands

Destruction of unhealthy host cells 31

References

• Basic Pathology 8th and 9th Edition, by Kumar, Cotran and Robbins

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