IMMUNOLOGY BASIC IMMUNOLOGY IMMUNE PATHOLOGY Éva Rajnavölgyi Department of Immunology.
Immunology Unit Department of Pathology Complement The complement system consists of about 20...
Transcript of Immunology Unit Department of Pathology Complement The complement system consists of about 20...
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
Main Functions of Complement
• Lysis of cell – Bacteria
• Generation of mediators– Participation in inflammation and attract
neutrophils
• Opsonization– Enhancement of phagocytosis
Antibody receptorbinding
Effector Mechanisms Against Extracellular Pathogens
OPSONISATION
OPSONISATION Phagocytosis
Bacteria in extracellular space
Ab
+
Effector Mechanisms Against Extracellular Pathogens
COMPLEMENT Activation
Bacteria in plasma
Ab & COMPLEMENT
+
Phagocytosis
binding
Complement &Fc receptor
Lysis
Opsonisation
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
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
• 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
C9 complex Complement-induced lesions on themembrane of a red blood cell
Kuby J et al., Immunology 2003
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)
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
Hereditary Angioedema
Immune complex disease
Recurrent bacterial infections
Recurrent Neisserial Infections
Clinical Syndromes Associated with Deficiencies of Complement Components
C1 Inhibitor
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)
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
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
Autocrine
Paracrine
Endocrine
General Properties of Cytokines Mode of Action
Close proximity
Distant cells
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- )
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.
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)
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
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
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