Immune responses

immune

1. IMMUNE RESPONSES

2. IMMUNE RESPONSES System of coordinated reaction of the cells of immune system and their products. 2 Types: Humoral or Antibody-mediated Immune Response ( AMI)- by secreting antibodies - neutralize microbial antigens (either circulating free or present on the surface of the host cells and in the extracellular spaces ) Cell-mediated Immune Response (CMI) – T cell mediated (especially cytotoxic T cells) various other effector cells such as NK cells, macrophages, granulocytes providing protection against intracellular microbes as well as tumor cells .

3. IMMUNE RESPONSES CMI and AMI cannot work individually- they are depended upon each other CMI regulates the humoral immunity by releasing cytokines from activated T cells that stimulate the B cells to transform into antibody secreting plasma cells Similarly, many effector cells of CMI such as macrophages and NK cells use antibodies as receptors to recognize the target cells for killing. certain initial events t ake place before the induction of either CMI or AMI. These events are common to both CMI and AMI Antigen presentation to helper T cells Activation and differentiation of helper T cells into either T H 1 or T H 2 subsets T H 1 cells secrete cytokines that stimulate CMI response , whereas if T H 2 cells secrete certain cytokines that in turn induce B cells to produce antibodies .

4. ANTIGEN PRESENTATION T cells can not recognize t he native and free antigens they recognized after the antigen is being processed in to smaller antigenic peptides containing specific epitopes and are combined with MHC molecules (class I or II)

5. Antigen-presenting Cells (APCs) presentation of antigenic peptide to both T H (helper T cells) and Tc (cytotoxic T cells) by complexing with MHC-II and I respectively. However APCs in strict sense implies only to those cells ( e.g dendritic cell, macrophage, etc.) that present the antigenic peptide along with MHC class II to T H cells Cells presenting antigenic peptides along with MHC class I molecules to Tc cells (virus infected cells or tumor cells) are not included under APCs Dendritic cells, macrophages and B cells are the major APCs and are called professional APCs . There are some other non-professional cells that can occasionally present antigens to helper T cells.

6. Antigen Processing Pathways For induction of immune response (both CMI and AMI ), antigens must be presented to T H cells. 2 well defined pathways used- Cytosolic pathway : endogenous (intracellular) antigens such as viral antigens and tumor antigens are processed and presented along with MHC class I molecules to CD8 T cells . Endocytic pathway : exogenous antigens (extracellular microbes and their products e.g. toxins) are processed and complexed with MHC class II molecules and presented to T cells. The cells involved are APCs such as macrophages, dendritic cells and B cells.

7. Over view of immune response

8. HELPER T CELLS (ACTIVATION AND DIFFERENTIATION) Helper T cell (T H ) activation and differentiation is the central event that regulates both the components of immune response- CMI and AMI. Signal Generation- Activation of T H cells requires generation of 2 specific signals- Antigen-specific signal: binding of antigenic peptide present in the groove of MHC-II on APCs to TCR (T cell receptor) present on surface of T H cells. CD4 molecules of T H cells also interact with beta2 domain of MHC II. Costimulatory signal: binding of CD28 molecule on T H cells to B7 molécules on APCs . APCs (macrophages) secrete interleukin-1 (IL-1) which acts on T H cells. Activation of T cell by interacting with APC

9. HELPER T CELLS (ACTIVATION AND DIFFERENTIATION) Signal Transduction initiated at CD4 molecule which interacts with CD3 complex, which in turn transmit the signal leading to activation of T H cells. Differentiation of Helper T cells Activated T H cells secrete increased amount of IL-2 as well as IL-2 receptor (IL2R or CD25). IL-2 binds to its receptors on the same T H cell and also on other T H cells and induces the naive T H cells to proliferate and differentiate. T H cells get activated and become lymphoblast cells which subsequently differentiate into memory and effector T H cells .

10. HELPER T CELLS (ACTIVATION AND DIFFERENTIATION) Effector T H cells derived either from the naive T H cells or preexisting memory T H cells differentiate into either T H 1 or T H 2 subsets. Cytokines secreted by T H 1 cell stimulate cytotoxic T cells and induce CMI response. cytokines secreted by T H 2 cell stimulate B cells to producing different classes of antibodies ( humoral immune responses ). IL 12 secreted by macrophage plays role in the differentiation of T H 1 cells.

11. HELPER T CELLS (ACTIVATION AND DIFFERENTIATION) T H 1 cells produce IL-2 interferon-y (IFN- y) and Tumor necrosis factor-b (TNF-b) T H 2 cells secrete IL-4 IL-5 IL-6 IL-10 and IL-13 Activate the B cells to transform into plasma cells- secrete antibodies Memory T Cells Derived from activated T H cell. Have longer life span (months to years ). Following subsequent antigenic stimulus, they become activated and differentiated into effector T H cells

12. CELL-MEDIATED IMMUNE RESPONSE For destruction of cells carrying intracellular microbes and other abnormal cells, such as tumor cells by various specific and nonspecific cells of immune system, of which the most important is cytotoxic T ( Tc )cells .

13. Effector Cells of CMI CMI can be mediated by both antigen specific and nonspecific effector cells . CD8 cytotoxic T lymphocytes (CTL or Tc ) are the principal effector cells - perform their function by direct killing of the target cells (e.g. virus infected cells or tumor cells). some nonspecific effector cells use antibodies as receptors to recognize the target cells for killing.

14. Activation of CTL Generation of activated CTL from naive Tc cells- requires induction of signals Antigen-specific signal: induced by binding of TCR-CD3 complex of naive Tc cells to MHC I –peptide complex of target cells. CD8 of Tc cells also interact with alfa3 domain of MHC-I. Costimulalory signal : CD28 of naïve Tc cells interacts with B7 molecule on target cells. Third signal : IL-2 ( secreted byT H 1 cell) acts on high affinity IL-2 receptor on Tc cells.

15. Functions of CTL (Target Cell Lysis ) The activated Tc , cells produce 2 types of lethal enzymes- Perforins produce pores in the target cell membrane; through which granzymes are released inside. Granzymes are serine proteases ; they induce cell death by apoptosis t hrough caspase pathway.

16. Natural Killer Cells derived from a separate lymphoid lineage. are cytotoxic, but antigen non-specific. They are part of innate immunity, act as first line of defence and do not require prior contact with the antigen. NK cell markers: lack t he T cell markers such as CD3, CD4 or CD8 molecules (hence are also called null cells ),but possess specific surface markers such as CD16 and CD56. No MHC restriction: can recognize the Ligands (antigens ) without MHC presentation .

17. HUMORAL/ANTIBODY-MEDIATED IMMUNE RESPONSE ( AMI ) provides protection to the host by secreting antibodies - that prevent invasion of microbes present on the surface of the host cells or in the extracellular environment, but has no role against intracellular microbes . AMI occurs through the following three sequential steps:

18. AMI Activation of B cells following contact with the microbial antigen- B cells act as APC . Proliferation and differentiation of B cells into effector cells- antibody producing plasma cells and memory cells. Effector function: secreted antibodies by plasma cells counter act with the microbes in many ways, such as neutralization. opsonization , complement activation, etc.

19. Activation of B Cells 2 categories Thymus dependent (TD)- Most antigens activate B cells indirectly via activation of T cells. TD antigens are processed by APCs, presented to T H cells following which the activated T H cells secrete cytokines that in turn activate the B cells. Thymus independen (TI )- antigens (e.g. bacterial capsule ) are not processed by APC. They can directly activate B cells without t he help of T cell induced cytokines

20. Antigen Presentation of B Cells to Activated T H Cells Recognition of microbial antigen (TD antigen ) by B cell membrane immunoglobulin receptors ( mlg ) followed by receptor mediated endocytosis of antigen . Then antigen is processed into smaller antigenic peptides tha t are presented in complex with MHC-II to activated T H cells ( by endocytic pathway ). This leads to induction of signals.

21. Signal Induction The naive B cells are in the resting stage. Activation requires induction of 3 signals Signal 1: induced by the cross linking of IgM on B cell membrane with microbial antigen . Signal 2: It is an additional signal provided by binding of CD40 on B cell with CD40L (ligand) on activated T H cells . Signal 3: It is usually a cytokine stimulus . Cytokines produced by the activated T H cells bind to specific cytokine receptor on B cells.

22. Signal Transduction Signal transduction is initiated by the 8-cell receptor (BCR). BCR comprises of 2 parts Antigen-binding membrane lg Ig- alfa / Ig-beta heterodimer Following antigen cross linkage to membrane Ig , heterodimer is activated and in turn transmits the signal, ultimately leading to activation of B cells.

23. Proliferation and Differentiation of B Cells Naive B cells , released from bone marrow- house in the B cell areas of peripheral lymphoid organs ( e.g. cortex of lymph node and marginal zone of spleen ). Following the antigenic exposure, the naive B cells are activated and then they proliferate. Eventually , primary lymphoid follicles transform into secondary lymphoid follicles. Ultimately Differentiation of centrocytes into plasma cells and memory cells:

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