Immunology Unit Department of Pathology
description
Transcript of Immunology Unit Department of Pathology
![Page 1: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/1.jpg)
Immunology UnitDepartment of Pathology
![Page 2: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/2.jpg)
Complement
• The complement system consists of about 20 proteins in normal human serum
• They are synthesized mainly by the liver
• Complement is heat labile i.e. it is inactivated at 56oC for 30 minutes
• Immunoglobulins are not inactivated at this temperature
![Page 3: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/3.jpg)
Main Functions of Complement
• Lysis of cell – Bacteria
• Generation of mediators– Participation in inflammation and attract
neutrophils
• Opsonization– Enhancement of phagocytosis
![Page 4: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/4.jpg)
Antibody receptorbinding
Effector Mechanisms Against Extracellular Pathogens
OPSONISATION
OPSONISATION Phagocytosis
Bacteria in extracellular space
Ab
+
![Page 5: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/5.jpg)
Effector Mechanisms Against Extracellular Pathogens
COMPLEMENT Activation
Bacteria in plasma
Ab & COMPLEMENT
+
Phagocytosis
binding
Complement &Fc receptor
Lysis
Opsonisation
![Page 6: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/6.jpg)
Complement Activation
• Several complement components are pro-enzymes and required cleavage to form active enzymes
• Activation of complement is initiated either by antigen-antibody complexes or by non-immunologic molecules such as endotoxin
![Page 7: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/7.jpg)
Complement Activation
• Pathways of activation– Classic Pathway– The Lectin Pathway– The Alternative Pathway
• Lectin and alternative pathways are activated with the first encounter with bacteria since the antibody required to trigger classic pathway is not present
![Page 8: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/8.jpg)
• Classic Pathway– Antigen-antibody complexes activate C1 to form
protease which cleaves C2 and C4 to form C4b,C2b complex
• The Lectin Pathway– Mannan-binding lectin (MBL) binds mannan present on
the surface of bacteria and cleaves C2 and C4 to activate classic pathway without the help of an antibody
• Alternative Pathway– Cell surface substances such as bacterial
lipoploysaccharides (endotoxin), fungal cell walls and viral envelopes can activate complement system directly by cleaving C3 into C3a and C3b
![Page 9: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/9.jpg)
Complement Activation Cascade
![Page 10: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/10.jpg)
Generation of C5 convertase leads to the activation of the
Lytic pathway
Lytic pathway
![Page 11: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/11.jpg)
Components of the lytic pathway
C6
C9
C8
C7C5
![Page 12: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/12.jpg)
Lytic pathwayC5-activation
C3b C2 aC4b
C5 b
C5a
![Page 13: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/13.jpg)
Lytic pathwayassembly of the lytic complex
C5 b
C6
C7
![Page 14: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/14.jpg)
Lytic pathway:insertion of lytic complex into cell membrane
C5 b
C6
C7C8
C9
C9
C9
C9C9
C9 C
9C9
C9
![Page 15: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/15.jpg)
C9 complex Complement-induced lesions on themembrane of a red blood cell
Kuby J et al., Immunology 2003
![Page 16: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/16.jpg)
Complement functions
• Host benefit:– Opsonization to enhance phagocytosis (C3b)– Phagocyte attraction and activation (C5a and
C5,6,7)– Lysis of bacteria and infected cells– Regulation of antibody responses– Clearance of immune complexes– Clearance of apoptotic cells
• Host detriment:– Inflammation – Anaphylaxis – mast cell degranulation (C3a, C4a,
C5a)
![Page 17: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/17.jpg)
Regulation of Complement System
• Antigen-antibody reaction is necessary for complement activation.
• C1 inhibitor
• Human cells are protected from lysis by membrane attack complex by “decay accelerating factor” (DAF) – DAF de-stabilizes C3 and C5 convertase to prevent the
formation of membrane attack complex
![Page 18: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/18.jpg)
Hereditary Angioedema
Immune complex disease
Recurrent bacterial infections
Recurrent Neisserial Infections
Clinical Syndromes Associated with Deficiencies of Complement Components
C1 Inhibitor
![Page 19: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/19.jpg)
Cytokines
![Page 20: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/20.jpg)
Cytokines
• Facts– They are low molecular weight proteins – They are involved in immunity and
inflammation where they regulate the amplitude and duration of inflammation
– They are extremely potent– They are produced transiently (short duration of
action)
![Page 21: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/21.jpg)
Cytokines
– They act with cell surface receptors specific for each cytokine group
– Individual cytokines have multiple overlapping cell regulatory actions and interact in the form of a network
• Synergistic and antagonistic actions
![Page 22: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/22.jpg)
Pleiotropic
Redundant
Synergistic
Antagonistic-
Cytokines : Mode of Action
![Page 23: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/23.jpg)
General Properties of Cytokines
• Cytokines induce their effects in three ways– Autocrine effect: ie, they act on the same cell that
produces the cytokine eg, IL-2– Paracrine effect: that effect other cells in the
vicinity eg, IL-7 in the bone marrow act on B cells progenitors
– Endocrine effect: they affect many cells systemically eg, IL-1 and TNF- which produce acute-phase response during inflammation
![Page 24: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/24.jpg)
Autocrine
Paracrine
Endocrine
General Properties of Cytokines Mode of Action
Close proximity
Distant cells
![Page 25: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/25.jpg)
Working Classification of Cytokines
• Cytokines that mediate natural immunity– Interleukin-1 (IL-1), tumor necrosis factor alpha
(TNF), interferons and IL-6
• Cytokines that regulate lymphocyte growth, activation and differentiation– IL-2, IL-4, IL-5, IL-12, IL-15 and transforming
growth factor- (TGF- )
![Page 26: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/26.jpg)
Working Classification of Cytokines
• Cytokines that activate inflammatory cells
– IFN-, TNF, lymphotoxin (TNF-) and migratory inhibitory factor
• Cytokines that affect leukocyte movements also called “chemokines”
– IL-8, Macrophage Inflammatory Protein (MIP), Macrophage Chemotactic Protein (MCP) etc.
![Page 27: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/27.jpg)
Working Classification of Cytokines
• Cytokines that stimulate hematopoiesis
– Stimulate the production of blood cells by acting on hematopoietic progenitor cells.
– The members of this family are called “colony-stimulating factors” (CSFs) eg, granulocyte-monocyte colony stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF)
![Page 28: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/28.jpg)
Cytokine ActionsIL-1 Activates T cells to produce IL-2
IL-2 Stimulates both helper and cytotoxic T cells
IL-4 and IL-5 They promote growth and differentiation of B cells respectively
IL-6 Stimulates B cell differentiation, induces fever
IL-8 Attracts neutrophils
IL-10 Inhibits the development of Th-1 by decreasing production of IF
IL-12 Promotes the development of Th-1 cells
IL-13 Mediates allergic inflammation in asthma
Transforming Growth Fctor beta (TGF-)
Anti-cytokine – inhibits growth and activities of T cellsPromotes synthesis of collagen (wound healing)
Chemokines Attract neutrophils and macrophages
Tumor Necrosis Factor (TNF)
Promotes neutrophil phagocytosis and killing, mediates extravascular migration of inflammatory cells
Interferones (INF) Block viral replication, Class switching of IgGs
![Page 29: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/29.jpg)
Disease Cytokines
Bacterial Septic Shock High TNF serum levels
Lymphoid and Myeloid Cancers
High levels of IL-6
T cell leukemia is associated with HTLV-1 retrovirus
Low levels of IL-2
Cytokines and Disease
![Page 30: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/30.jpg)
Cytokine Related Therapies
• Soluble form of IL-1 receptor inhibits Th cell activation – prolongs graft survival in heart transplantation
• IL-2 conjugated with toxin diminishes rejection of kidney and heart transplants
• Lymphokine activated killer cells in tumor therapy
• Antibody to IL-4 reduces IgE production
![Page 31: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/31.jpg)
Cytokine Network
• Targets
![Page 32: Immunology Unit Department of Pathology](https://reader036.fdocuments.in/reader036/viewer/2022062408/568144a1550346895db162a2/html5/thumbnails/32.jpg)
Thank you