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regulation of leukocyte mediated cytotoxicity

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate, or extent of leukocyte mediated cytotoxicity. [GOC:add, ISBN:0781735149, PMID:11911826]

Leukocyte-mediated cytotoxicity is a complex process involving the coordinated action of various immune cells to eliminate target cells, such as infected cells or tumor cells. This process is tightly regulated to ensure that only appropriate targets are destroyed, while healthy cells are spared. Here's a detailed breakdown of the biological process:

**1. Recognition of Target Cells:**

* **Antigen Presentation:** Immune cells like macrophages and dendritic cells engulf and process antigens from pathogens or tumor cells. They then present these antigens on their surface using MHC (major histocompatibility complex) molecules.
* **T Cell Activation:** CD8+ T lymphocytes (cytotoxic T lymphocytes or CTLs) recognize antigen-MHC complexes on target cells through their T cell receptors (TCRs). This interaction, along with signals from co-stimulatory molecules, activates the T cell.

**2. Signal Transduction and Polarization:**

* **Activation of Signaling Pathways:** TCR engagement triggers a cascade of intracellular signaling pathways, leading to the production of transcription factors that regulate gene expression in the T cell.
* **Polarization:** Activated T cells undergo cytoskeletal reorganization, forming an immunological synapse with the target cell. This involves the localization of cytotoxic molecules (e.g., perforin and granzyme) towards the contact site.

**3. Cytotoxic Molecule Delivery:**

* **Exocytosis:** T cells release cytotoxic molecules, including perforin and granzymes, from specialized secretory granules. These molecules are directed towards the target cell through the immunological synapse.
* **Perforin:** Perforin forms pores in the target cell membrane, disrupting its integrity and allowing the entry of granzymes.
* **Granzymes:** Granzymes are proteases that enter the target cell through the perforin-created pores. They activate apoptotic pathways, leading to programmed cell death.

**4. Cell Death and Clearance:**

* **Apoptosis:** Granzyme-induced caspase activation triggers a cascade of events that dismantle the target cell's internal structures, leading to its fragmentation.
* **Phagocytosis:** Phagocytic cells, such as macrophages, engulf and digest the apoptotic fragments, removing them from the body.

**5. Regulatory Mechanisms:**

* **Immune Checkpoint Molecules:** To prevent excessive cytotoxicity and autoimmunity, inhibitory receptors (e.g., CTLA-4, PD-1) are expressed on activated T cells. These molecules interact with ligands on antigen-presenting cells or target cells, downregulating T cell activation and preventing excessive killing.
* **Cytokine Regulation:** Cytokines, such as IL-2 and IFN-gamma, play a role in fine-tuning the immune response by regulating the activation, differentiation, and survival of various immune cells.

**6. Role of Natural Killer (NK) Cells:**

* **NK Cell Recognition:** Natural killer (NK) cells are innate immune cells that can kill target cells without prior sensitization to specific antigens. They recognize and eliminate target cells that lack MHC expression or display stress signals, such as tumor cells or virally infected cells.
* **NK Cell Mechanisms:** NK cells utilize cytotoxic mechanisms similar to CTLs, including the release of perforin and granzymes.

**7. Dysregulation and Implications:**

* **Autoimmune Diseases:** Dysregulation of leukocyte-mediated cytotoxicity can lead to autoimmune diseases, where the immune system attacks healthy tissues.
* **Cancer:** Defects in immune surveillance mechanisms, including leukocyte-mediated cytotoxicity, can contribute to cancer development and progression.
* **Infections:** Impaired leukocyte-mediated cytotoxicity can increase susceptibility to infections and hinder the ability to control pathogen spread.

This intricate process ensures the effective elimination of harmful cells while minimizing collateral damage to healthy tissues. The balance between activation and inhibition of leukocyte-mediated cytotoxicity is crucial for maintaining immune homeostasis.'
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Proteins (1)

ProteinDefinitionTaxonomy
Intercellular adhesion molecule 1An intercellular adhesion molecule 1 that is encoded in the genome of human. [PRO:WCB, UniProtKB:P05362]Homo sapiens (human)

Compounds (13)

CompoundDefinitionClassesRoles
indoleindole;
polycyclic heteroarene
Escherichia coli metabolite
1,4-benzodioxan1,4-benzodioxan: structure in first source
1-methylindole1-methylindole: SKATOLE refers to 3-methylindole; RN given refers to parent cpd; structure

methylindole : Any member of the class of indoles carrying one or more methyl substituents.
lovastatinlovastatin : A fatty acid ester that is mevastatin carrying an additional methyl group on the carbobicyclic skeleton. It is used in as an anticholesteremic drug and has been found in fungal species such as Aspergillus terreus and Pleurotus ostreatus (oyster mushroom).

Lovastatin: A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (HYDROXYMETHYLGLUTARYL COA REDUCTASES), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver.
delta-lactone;
fatty acid ester;
hexahydronaphthalenes;
polyketide;
statin (naturally occurring)
anticholesteremic drug;
antineoplastic agent;
Aspergillus metabolite;
prodrug
chlorfenethazinechlorfenethazine: RN given refers to parent cpd; synonym elroquil refers to HCl; structurephenothiazines
2-bromohippuric acid
benzotriptbenzotript: anti-gastrinic; active group is amide; structure
pd 144795
birt 377
4-[(4-methylphenyl)thio]-2-thieno[2,3-c]pyridinecarboxamidearyl sulfide
a 286982A 286982: inhibits the interaction between leukocyte function-associated antigen-1 and intracellular adhesion molecule-1; structure in first source
bio 1211BIO 1211: integrin alpha4beta1 inhibitor; structure in first source
sar 1118lifitegrast : An N-acyl-L-alpha-amino acid obtained by formal condensation of the carboxy group of N-[2-(1-benzofuran-6-carbonyl)]-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid with the amino group of 3-(methanesulfonyl)-L-phenylalanine. Used for treatment of keratoconjunctivitis sicca (dry eye syndrome).

lifitegrast: An LFA-1 (LYMPHOCYTE FUNCTION-ASSOCIATED ANTIGEN-1) antagonist that is used in the treatment of DRY EYE SYNDROMES.
1-benzofurans;
isoquinolines;
L-phenylalanine derivative;
N-acyl-L-alpha-amino acid;
sulfone
anti-inflammatory drug;
lymphocyte function-associated antigen-1 antagonist