1. Cells of the Immune System
Dr. Raid Jastania

2. Intended Learning Outcomes:
Students should be able to describe the immune system and the cellular interactions involved in humoral and cellular immunity.
Students should have a clear understanding of major histocompatibility complex (MHC) molecules and their role in immunity.
Students should be able to list the hypersensitivity reactions, and discuss the basic mechanism of them and give few examples of each type.
Students should understand how “Tolerance” occurs and how failure of tolerance may result in autoimmune diseases
Students should have a clear understanding of the pathogenesis of autoimmune diseases, and know the features of SLE.
Students should have a general brief understanding of immunodeficiency.

3. Diseases of the immune system:
There are 3 types or categories of diseases of the immune stystem:
Hypersensitivity reactions
Autoimmune diseases
Immunodeficiency

4. Definitions Central immune system: bone marrow and thymus
Peripheral immune system: any site except bone marrow and thymus, it is mainly peripheral blood, lymph and lymph nodes, spleen and mucosa of GIT, respiratory system and genitourinary system.
Peripheral Lymphocytes: Lymphocytes not in the central part of the immune system (not in bone marrow or thymus)
Naïve cell: used to describe newly produced lymphocytes that have not encounter antigens.

5. Definitions
Transformed cell: changes of the morphology of lymphocytes when they encounter antigen and start the process of adaptive immunity.
Maturity and Differentiation and CD’s: The lymphocytes pass through different stages of maturation. During each stage, they express certain molecules on the cell surface (or in the cytoplasm). These molecules are named cluster of differentiation (CD). CD’s may appear at one stage then disappear at another.

6. Definitions
TCR: T-cell receptor is the molecule that T cells can recognize antigens with and start adaptive response.
BCR: B-cell receptor is IgM molecule that binds to antigens to stimulate B-cells.
APC: antigen presenting cell, including macrophages, monocytes, dendritc cells, and B-cells.

7. Cells of the Immune system
T-lymphocytes:
Thymus-derived
Mediate and control immunity
60-70% of circulating lymphocytes
Found in the thymus, lymph nodes, spleen
TCR (T cell receptor) recognizes specific antigen
TCR needs somatic rearrangement to be unique for antigens

8. T-cells
TCR consists of alpha and beta chains, each has variable region and a constant region
There is gamma, delta TCR as well, less in number, found in mucosa
TCR is accompanied by CD3 (consists of alpha, delta, and epsilon chains) and 2 zeta chains.
CD4 and CD8 subsets: CD4+ is T helper cell. CD8+ is T cytotoxic cell.

9. T-cells T helper is further divided to two subtypes:
T-h1: mediate cellular immunity by secreting IL-2, and IFN-gamma
T-h2: mediate humoral immunity by secreting IL-4, IL-5, IL-10

10. T-cells The interaction of T-cells with APC’s needs 2 signals:
TCR binds to antigen, and CD4/8 binds to MHC-II/I
CD28 binds to B7-1 or B7-2
In the absence of the second signal, T-cell either die or be inactivated (anergy)

11. B-lymphocytes Bone marrow-derived 10-20% of circulating lymphocytes
Found in lymph, and lymph nodes, spleen tonsils and all mucosal surfaces.
BCR is IgM molecule that binds to antigens
The final step of maturation is plasma cell which secrete antibodies.
There are 5 classes of anibodies: IgG, IgM, IgE, IgA, IgD
CD21 is the receptor for EBV.

12. B-lymphocytes
The Journey of B-cells

13. Macrophages APC: antigen presenting cell. Processing and presentation
Express MHC-II that interact with CD4+ T-cells
Secrete cytokines
Kill microbes coated by antibodies and complement

14. Dendritic Cells
Interdigitating dendritic cells are found in lymphoid organs, interstitial tissue of visceral organs eg. Lung, skin.
Follicular dendritic cells: express Fc receptor that binds to Ag-Ab complex

15. Natural Killer Cells 10-15% of peripheral lymphocytes
can lyse cells without previous sensitization
express Killer Inhibitor Receptor (KIR). When KIR binds to MHC-I it prevents killing
CD16 is Fc receptor
Mediate Antibody-dependent Cell-mediated Cytotoxicity

16. Major Histocompatibility Complex (MHC), Human Leukocyte Antigen (HLA)
MHC or HLA are molecules that are expressed on the cell membrane of cells. They are polymorphic and each person has a unique MHC.
They were first described in transplant rejection and called HLA
MHC restriction means that T-cells do not recognize antigens unless they are presented by APC with MHC.

17. MHC, HLA:There are 3 main classes
Class I: MHC-I:
are encoded in Chromosome 6
HLA-A, HLA-B, HLA-C
The extracellular portion contains cleft for Ag presentation to CD8+ T-cells
Class I is present on all nucleated cells
Generally it presents proteins that have been synthesized in the cell eg. Viral proteins

18. Class II: MHC-II:
HLA-D (HLA-DP, HLA-DQ, HLA-DR)
The extracellular portion contain cleft for Ag binding and presentation to CD4+ T-cells
Expressed on APC (monocytes, macrophages, dendritic cells) and B-cells.
May be expressed on other cells if induced by IFN-gamma, eg. Endothelium, fibroblasts, renal tubular epithelium.
It generally binds and present proteins that come from outside the cell, eg. Bacterial proteins

19. Class III: MHC-III:
Include some of the complement components C2, C3 and TNF
They are not Histocompatibility molecules

20. Diversity of MHC Class I: 6 different molecules (genes) in a person
Class II: each molecule consists of alpha and beta chains, can give 20 different combination in a person.
Overall: innumerable combination of molecules that give a person unique MHC
HLA typing is done for organ transplantation
There is different ability of MHC’s (and persons) to bind and present antigens, and hence different immune response.

21. HLA and disease association
Many diseases are associated with selected HLA type
Example: ankylosing spondylitis associated with HLA-B27 with 90x increase risk of developing the disease
HLA is associated with 3 groups of diseases:
Inflammatory diseases, eg. Ankylosing spondyliti
Inherited errors of metablolism, eg. 21-hydroxylase deficiency (HLA-BW47)
Autoimmune diseases, eg. Rheumatoid arthritis

22. Cytokines Low molecular weight polypeptides
Secreted by lymphocytes and monocytes
Less secreted by epithelial and mesenchymal cells
Act on receptors, eg. IL-2 acts on IL-2R
Act by autocrine, paracrine and endocrine fashion
Different action on different cells
Eg. IL-2 activate T-cells, and regulate B-cells
Some of them are antagonists, eg. IFN-gamma opposes IL-10

23. Classes of Cytokines
Cytokines that mediate innate immunity: eg. IL-1, TNF, IL-6
Cytokines that regulate lymphocyte growth, activation and differentiation, eg. IL-2, IL-4, IL-5, IL-12, IL-15, TGF-alpha
Cytokines that activate inflammatory cells, eg. IFN-gamma, TNF
Chemokines: mediate chemotaxis, IL-8 attract neutrophils, IL-5 attract eosinophils
Cytokines that stimulate hematopoiesis, eg. GM-CSF granulocyte and macrophage colony stimulating factor