Ø  CMI- immune reactions in which T cells play a central role as effector cells instead of regulatory cells

• includes T-cell cytotoxicity and Delayed type Hypersensitivity
• Granulomatous responses usually result from DTH reactions to poorly degradable antigens, although Ab responses can also be involved.

T Cell Cytotoxicity

• T mediated cellular cytotoxicity involving direct contact between the effector cell (T_CTL) and a target cell, resulting in cell lysis or apoptosis

Mechanisms

1. Generally involves CD8+ T cells   (Contrary to the norm there are some cytotoxic CD4 T cells.

2. CD8+ T cells must become activated by Ag-MHC-I complexes and IL-2 produced by T Helper cells and thereafter undergo proliferation and differentiation into active T_CTL cells

3. specific TCR on the T_CTL binds to the Ag-MHC I complex on the surface of the target cell.  Also there is another protein called fas on the target cell which binds to fas ligand on the T_CTL­.  There are also other accessory protein bridges formed.

4. Binding of the TCR activates the release of  granules containing perforin and granzymes by the T_CTL.  Most of these bind to the target cell.

5. Perforin- forms pore; similar to C9; in enough pores are formed—lysis occurs

6. Cytokines released by the T_CTL (IFN-g and TNF-a) may have cytotoxic effects of the targeted cell.

7. Apoptosis can also occur.  This is activated by two signals.  1^st- the binding of fas to the fas ligand and 2^nd- the leakage of granzymes into the target cell.

8. These two signals induce the target cell to produce two proteases called interleukin converting enzyme and Yama (Hindu god of death).

9. These two enzymes are what causes the apoptosis; irreversible

10. Once targeted cell is reprogrammed to die, T_CTL can move on to the next Ag

11. Null lymphocytes can do this too.

12. Bcl-2- protein in some targeted cells which prevents the activation of ICE—blocks apoptosis.

Medical Aspects

1.     Protective

a.     Viral infections- T cell mediated cytotoxicity seems to be the #1 way to eliminate virally infected cells

b.     Cancer- elimination of malignant cells before they proliferate-immune surveillance-

c.      Intracellular pathogens- can kill malaria

Immunopathology

1.     Autoimmune diseases- IDDM; Hashimoto’s thyroiditis

2.     Contact dermatitis-

3.     Viral exanthems- eruptive lesions and fever of many viral infections are due to host immune response

4.     Graft rejection-

cRelease Assay

• way to measure cytotoxic activity

Delayed Type Hypersensitivity (DTH)  Type IV Hypersensitivity

• in vivo reaction involving activation of macrophages by cytokines produced by lymphocytes (T_DTH)
• Type IV hypersensitivity

Mechanisms

1.     T cells are stimulated by TCR interaction w/ Ag-MHC II complexes on the surface of APCs.

2.     They also have to undergo proliferation, differentiation, and activation

3.     Upon restimulation, The resulting memory T_DTH cells express:

a.     IL-2- activates additional T cells

b.     Macrophage Chemotactic factor (MCF)- attracts macrophages

c.      IFN-g- activates macrophages

d.     TNF-b- can be cytotoxic

4.     It takes 1-2 days even in a sensitized individual to get significant numbers—–DTH

5.     Main activity- recruitment and activation of macrophages

6.     DTH reactions can be inhibited by corticosteroids, or cyclosporin.  These are commonly used to control autoimmune diseases and transplant rejection.

Medical Aspects

Protective

1. Destruction of intracellular bacteria and other pathogens

• DTH is #1 against mycobacterial and most parasitic and fungal infections

2. Cancer

• Immune surveilance

Immunopathology

1.     Contact hypersensitivity- skin reaction to certain environmental agents (poison ivy, rubber, latex, PABA)

2.     Autoimmune diseases- MS, IDDM, Hashimoto’s thyroiditis, rheumatoid arthritis (most are mixtures)

3.     Transplant rejection- active in acute allograft rejection

Blast transformation assays

• in vitro measures of T cell reactivity

Granulomatous Reactions

• space-occupying lesion consisting of a predominantly mononuclear infiltrate (lymphs and macs) at the site of disposition of a poorly degradable antigen.

Mechanisms

1.     Usu. caused by DTH reactions,  architype is the granuloma characteristic of tuberculosis

2.     CD4+ and macs accumulate at the site of Ag in a typical DTH response

3.     If Ag not easily degraded, it will persist and cause continued accumulation of cells

4.     This resulting granuloma contains epitheloid cells(large macs) and multinucleate giant cells (formed by fusion of mac cells)

5.     Can cause fibrosis and become necrotic

Medical Aspects

1.     Mycobacterial infections- TB and leprosy; granulomas can be detected in CXR and are indicative of past or present infection

2.     Parasitic infections- can cause elephantitis

3.     Sarcoidosis- disease of unknown etiology causing multiple granulomas in different sites.

4.     Crohn’s disease- inflammatory disease of the bowel; granulomas cause obstruction and fistula formation.

Tags: (DTH) Type IV Hypersensitivity, Apoptosis, Autoimmune diseases, cellular cytotoxicity, Contact dermatitis, Crohn's disease, Cytokines, cytotoxic activity, granulomas, Granulomatous responses, Hashimoto's thyroiditis, immune reactions, Lymphocytes, Macrophage Chemotactic factor, Mycobacterial infections, Rheumatoid arthritis, Sarcoidosis, T-cell, Viral exanthems, Viral infections

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