Overview Immune system

KK HARIS, GDC, Raipur.

to the

The Immune system

=defence system Latin word immunis= state of protection from infectious disease. Plaque epidemic (430 BC): Those who recovered from plaque could nurse the sick patients safely.

Immunity

Innate Immunity (natural)

Adaptive Immunity (acquired)

Innate immunity
First line of defence against infection Anatomical barriers: skin & mucous membranes

Acidity of stomach contents kills microorganisms

After enterance into the body Phagocytosis: blood monocytes, neutrophils and tissue macrophages- Phagocytose, kill, and digest whole organisms.

Complement lyses microorganisms/facilitates Phagocytosis

Anatomic barriers

Skin lining (Epidermis & Dermis) Sebaceous glands in the skin, associated with the hair follicles. Produce sebum (oily secretion)= consist of lactic acid and fatty acids, PH 3-5, that inhibits growth of microorganisms.

Mucous membranes: (epithelial & CT layers) conjunctivae (eye) Alimentary, Respiratory & Urogenital tracts

Wash effect of tears, saliva & mucous secretion. Mucous secretion: entraps foreign microorganisms. Lower respiratory tract: cilia (hair-like protrusions of epithelial cells), Propels mucous entraped microorganisms. Lysozymes (mucous, tears): destroy bacterial cell wall

Phagocytosis:
Phagocytic Cells: Monocytes, neutrophils and tissue macrophages. Internalization of whole micoorganism and formation of Phagosomes. Fusion of phagosomes with lysosome

Digestion of microorganism by lysosomal enzymes

How do lysosomes destroy microbes?

The lysosome has two ways of killing trapped microbes
Generating toxic form of oxygen Using degrading enzymes or killing proteins

There are microbes that have evolved mechanisms for evading phagocytic destruction
Some bacteria have outer capsules to which a macrophage cannot attach

Haemophilus influenzae type b, Streptococcus pneumoniae Mycobacterium tuberculosis (pneumococcus), Neisseria meningitides (meningococcus), Group B streptococcus
Some others are readily engulfed, but are resistant to lysosomal destruction and can even reproduce inside a macrophage

Mycobacterium tuberculosis These microorganisms are a particular problem for both nonspecific and specific defenses of the body

The complement system

A group of serum proteins Circulate in functionally inactive forms (pro-enzymes). Examples C1, C2, C3,C9. Activation of the complement system results in damaging the cell wall of microorganisms

Adaptive immunity (acquired)

Ability to RECOGNIZE and selectively eliminate SPECIFIC foreign microorganism.

Different from Innate Immunity: characterized by, Specificity Immunological memory

Adaptive/acquired Immunity

Mediated by lymphocytes
T-lymphocytes (T-cells) B-lymphocytes (B-cells)

(antigen-presenting cells)

Lymphocytes are produced at the bone marrow.

B lympocytes mature in Bone marrow.

T lymphocytes differentiate and mature in the thymus

i.e. Bone marrow & Thymus= primary lymphoid organs.

Sites for immune response:

Lymph nodes (lymph) Spleen (blood born) Antigens are taken by Antigen presenting cells, presented to T cells. B lymphocytes see the antigen directly.

Lymph nodes and spleen= secondary lymphoid organs.

Organs of the immune system (classification)

Bone marrow

Primary immune (lymphoid) organs

Thymus

Spleen Lymph nodes

Secondary immune (lymphoid) organs

Tonsils
Peyers patches (GIT) Appendix

Organs of adaptive immunity

White pulp

Red pulp Vein

Germinal center Artery

Lymphocyte classes
B lymphocyte
(B cell)

T helper cell

T lymphocyte
(T cell)

T cytotoxic cell

Natural Killer cell

(Large granular lymphocyte) (NK cell)

Lymphocytes provide the specificity and diversity of the immune system There are two main types of lymphocytes: B lymphocytes (B cells) and T lymphocytes (T cells): Cytotoxic T (Tc) cells, Helper (Th) T cells BCR TCR TCR

CD8

CD4

B cell

Cytotoxic T cell

Helper T cell

Both types of lymphocytes circulate throughout the blood and lymph and are concentrated in the spleen, lymph nodes, and other lymphatic tissue

Lymphocytes show specificity

Because T and B lymphocytes recognize and respond to particular microbes and foreign molecules, they are said to display specificity.

What is an immunogen?
A foreign molecule that elicits a specific response by Lymphocytes is called an immunogen. What is an antigen? A foreign molecule that binds specifically to an antibody, a B cell or a T cell receptor.

B-lymphocytes produce Immunoglobulin (=antibodies).

Humoral Immunity

Immunoglobulins
Immunoglobulin G (IgG) Immunoglobulin M (IgM)
secondary Immune response

Primary Immune response

Immunoglobulin A (IgA)
Immunoglobulin E (IgE)

mucosal Immunity

Allergic reaction

(Immunoglobulin D)

IgG: opsonization, complement activation IgM: Complement activation IgA: mucosal Immunity IgE: allergic reaction

Neutralization (IgG)

T-lymphocytes mediate cellular immune mechanisms.

Cellular Immunity T-helper Cytotoxic

T-lyphocytes have two subpopulations

T-helper cells (secrete growth factors called CYTOKINES), give help to other cells e.g. B-cells to produce immunoglobulin (antibodies), OR Give help to cytotoxic T-cells/ macrophages. T-cytotoxic cells (secrete toxic substances to destry infected cells).

T-helper cells see foreign antigen on microorganisms as presented by ANTIGEN PRESENTING CELLS (APC).

Immune system (conclusion) Innate Immunity (skin/mucous membranes & low PH, complement system & Phagocytosis) Acquired Immunity (T- and B-lymphocytes & B-lymphoctes secrete immunoglobulin and T-cells are either helper or cytotoxic T-lymhocytes). Organs of the immune system are either: Primary: Thymus, bone marrow OR Secondary: Lymph nodes, spleen, ..etc

Functions of Immunoglobulins:
Neutralization of microbes or toxins Opsonization Activation of complement system Antibody dependent cytotoxicity (ADCC): type II hypersensitivity reaction IgE (cross reactivity of receptors on mast cells, release of allergy mediators).

1. 2. 3. 4.

5.

Functions of antibodies The binding of antibodies to antigens to form antigen-antibody complexes is the basis of several antigen disposal mechanisms

T lymphocytes B lymphocytes
1. 2.

Effector cells Memory cells

Humoral Immune Responses

An APC engulfs a bacterium (an exogenous antigen), degrades it and transports a fragment of it to the cell surface via a class II MHC molecule A specific TH cell is activated by binding to the MHC-antigen complex on the surface of the APC
3
Memory T cell

The humoral immune response is initiated when B cells bearing antigen receptors are selected by binding with specific antigens

( Th1, Th2 cytokines)

In this process of clonal selection, each antigen, by binding to specific receptors selectively, activates a tiny fraction of cells from the bodys diverse pool of lymphocytes

Cell mediated Immune Responses

Cell mediated immune responses are mounted against virus or intracellular bacteria infected cells These intracellular infectious agents produce proteins that can be presented by MHC class I molecules to cytotoxic T cells (CD8+ T cells) The interaction between antigen loaded MHC class I and Tc-receptor leads to activation, proliferation and differentiation of Tc cells Tc cells also need the cytokine help from Th1 cells in order to be activated
Th1 cytokines

Activated Tc cells will differentiate to active killer, which kill infected target cells by releasing perforin

Mechanism of cytotoxic T cell mediated killing

Granzyme B

Induction of apoptosis by granzyme B

Extracellular micro-organisms: bacteria, helminthic infections,..etc= humoral Immunity N.B. Exogenous antigen Intracellular: bacteria or viruses, also in case of Cancer= cellular immunity -cytotoxic cells (CD8+ cells) -Natural Killer cells (NK cells) N.B. Endogenous antigen

T helper cells= CD4+ T cells

T cytotoxic cells= CD8 + T cells

NK cells= CD56/CD16 CD19= B cells

Th cells secrete cytokines e.g. IFN-gamma= Th1 cells IL-4, IL5, IL-13,etc = Th2 cells IL = Interleukin (cytokine) Interferon gamma=IFN-g Cytokines= mediate communications within the Immune system.

Th1 secrete IFN-gamma: activation of phagocytic cells) macrophage activator), also activation of other cytotoxic cells Th2 secrete: IL-4: B lymphocytes

Th1 and Th2 cytokines and their functions

Cytokine/function

Th1
Secretion ++ ++ ++ Functions

Th2
++ ++ ++

Interleukin 2 (IL-2) Interferon g (IFN-g) TNF-b IL-4 IL-5 IL-13

Help for antibody production Mast cell activation Cytotoxic T cell activation

++

++ ++ -

Humoral and Cell mediated Immune Responses in brief

Major Histocompatibility complex

Major histocompatibility complex (MHC) was discovered as an extended locus containing highly polymorphic genes that determined the outcome of tissue transplants exchanged between individuals.
In humans the MHC is called Human leucocyte antigens (HLA)

HLA Class I & II Structure

MHC=HLA

Antigen presentation (MHC-I)

Antigen presentation (MHC-II)

MHC-restriction

What is MHC restriction?

T cells of an individual can see peptidesantigens only when these peptides are displayed by that individual's MHC molecules (i.e. self MHC molecules). T cells has dual specificity: The T cell receptor (TCR) recognizes the peptide antigen and also recognizes the MHC molecule.

MHC class I
HLA-A HLA-B HLA-C

MHC class II
HLA-DR HLA-DQ HLA-DP

The MHC is a genetic locus whose principal products function as the peptide display molecules of the immune system.

They can also be recognized by the immune system as foreign antigens in transplanted organs.

Antigen presenting cells (APC) capture microbial antigens and present them for recognition by T lymphocytes. Professional APC: Dendritic cells, Macrophages, B cells

APCs present antigens in the context of MHC class II. Seen by CD4+ T cells.

Infected host cells present antigens of intracellular microbes in the context of MHC class I.
CD8+ T cells recognize viral antigens (e.g.) presented in the context of MHC class I.

Transplantation of organs:

If HLA antigens are different between individuals, the recipient my mount an immune response to the foreign HLA antigens in the donors tissues.

Antibodies and T cells react against the foreign HLA antigen/s may result in graft rejection.

CD3 Complex With TCR

TCR
Recognition

CD3

CD3

+ + +

- -

- Signaling

Signals that result in T cell Activation

Signal I: MHC-Ag- TCR-CD3 Signal II: CD28-- B7

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