Dr. Prem Mohan Jha presented on complement physiology. The complement system is part of the innate immune system and helps antibodies clear pathogens. It involves a biochemical cascade that is activated via three pathways: classical, lectin, and alternative. Complement activation leads to the formation of the membrane attack complex (MAC) which lyses cells. The complement system is tightly regulated to prevent damage to host cells. Deficiencies in complement components or regulators result in increased susceptibility to infections.
The complement system is a part of the immune system that helps or complements the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the innate immune system, which is not adaptable and does not change over the course of an individual's lifetime.
consists of three pathways: 1. alternative
2. classical
3. lectin pathway
The document summarizes the complement system. It is part of the immune system and consists of proteins that interact in a regulated cascade to eliminate pathogens and damaged cells. There are over 20 complement proteins that are activated via the classical, alternative, or lectin pathways and work in both innate and adaptive immunity. The complement system opsonizes pathogens, causes cell lysis, promotes inflammation, and clearance of immune complexes. Deficiencies or dysregulation of complements can cause diseases.
The document discusses the complement system, which consists of over 30 proteins produced by the liver that function in the immune system but are not antibodies. It works as a cascade system where one activation triggers another in a chain reaction. Complement activation can lead to cell lysis and generation of inflammatory substances. It plays a role in defense against bacteria and in inflammatory and autoimmune diseases. There are three complement activation pathways: classical, alternative, and lectin. The classical pathway is antibody-dependent while the alternative and lectin pathways are antibody-independent. Complement activation results in opsonization, inflammation, clearance of immune complexes, and lysis of pathogen cells.
Immune tolerance is induced through central and peripheral mechanisms that eliminate or suppress self-reactive immune cells. Central tolerance occurs in the thymus and bone marrow where high-affinity self-reactive T and B cells undergo apoptosis or receptor editing. Peripheral tolerance includes anergy induction, suppression by regulatory T cells (Tregs), and inhibition by receptors like CTLA-4 and PD-1. Tregs expressing the transcription factor FoxP3 are critical for maintaining tolerance and preventing autoimmunity. Failure of these tolerance mechanisms can lead to autoimmune disease.
The document summarizes the humoral immune response. It involves B cells producing antibodies that destroy extracellular microorganisms and prevent spread of intracellular infections. The process begins when a bacterium is phagocytosed by an antigen presenting cell. The antigen is processed and displayed on the cell surface. This activates helper T cells, which trigger B cell activation and antibody production. The antibodies then bind to antigens on microorganisms, marking them for destruction by immune cells and complement proteins.
Antigen presenting cells such as dendritic cells, macrophages, and B cells play a key role in activating T cells during an immune response. They process foreign antigens, display antigen fragments on MHC molecules, and present these to T cells. This initiation of T cell activation requires two signals: 1) antigen recognition by T cell receptors and 2) co-stimulatory signaling between molecules on the antigen presenting cell and T cell. Together, these signals trigger T cells to proliferate and carry out their immune functions in fighting pathogens or cancer cells.
The document discusses T lymphocytes and their generation, maturation, activation, and differentiation. It provides details on:
1) T-lymphocytes mature in the thymus gland and express T-cell receptors that recognize antigens bound to MHC molecules. They differentiate into helper T-cells, cytotoxic T-cells, memory T-cells, and regulatory T-cells.
2) T-cell receptors are composed of alpha and beta chains that undergo gene rearrangement during development.
3) T-cells mature through double negative, double positive, and single positive stages in the thymus, undergoing positive and negative selection to remove self-reactive cells.
The complement system is a part of the immune system that helps or complements the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the innate immune system, which is not adaptable and does not change over the course of an individual's lifetime.
consists of three pathways: 1. alternative
2. classical
3. lectin pathway
The document summarizes the complement system. It is part of the immune system and consists of proteins that interact in a regulated cascade to eliminate pathogens and damaged cells. There are over 20 complement proteins that are activated via the classical, alternative, or lectin pathways and work in both innate and adaptive immunity. The complement system opsonizes pathogens, causes cell lysis, promotes inflammation, and clearance of immune complexes. Deficiencies or dysregulation of complements can cause diseases.
The document discusses the complement system, which consists of over 30 proteins produced by the liver that function in the immune system but are not antibodies. It works as a cascade system where one activation triggers another in a chain reaction. Complement activation can lead to cell lysis and generation of inflammatory substances. It plays a role in defense against bacteria and in inflammatory and autoimmune diseases. There are three complement activation pathways: classical, alternative, and lectin. The classical pathway is antibody-dependent while the alternative and lectin pathways are antibody-independent. Complement activation results in opsonization, inflammation, clearance of immune complexes, and lysis of pathogen cells.
Immune tolerance is induced through central and peripheral mechanisms that eliminate or suppress self-reactive immune cells. Central tolerance occurs in the thymus and bone marrow where high-affinity self-reactive T and B cells undergo apoptosis or receptor editing. Peripheral tolerance includes anergy induction, suppression by regulatory T cells (Tregs), and inhibition by receptors like CTLA-4 and PD-1. Tregs expressing the transcription factor FoxP3 are critical for maintaining tolerance and preventing autoimmunity. Failure of these tolerance mechanisms can lead to autoimmune disease.
The document summarizes the humoral immune response. It involves B cells producing antibodies that destroy extracellular microorganisms and prevent spread of intracellular infections. The process begins when a bacterium is phagocytosed by an antigen presenting cell. The antigen is processed and displayed on the cell surface. This activates helper T cells, which trigger B cell activation and antibody production. The antibodies then bind to antigens on microorganisms, marking them for destruction by immune cells and complement proteins.
Antigen presenting cells such as dendritic cells, macrophages, and B cells play a key role in activating T cells during an immune response. They process foreign antigens, display antigen fragments on MHC molecules, and present these to T cells. This initiation of T cell activation requires two signals: 1) antigen recognition by T cell receptors and 2) co-stimulatory signaling between molecules on the antigen presenting cell and T cell. Together, these signals trigger T cells to proliferate and carry out their immune functions in fighting pathogens or cancer cells.
The document discusses T lymphocytes and their generation, maturation, activation, and differentiation. It provides details on:
1) T-lymphocytes mature in the thymus gland and express T-cell receptors that recognize antigens bound to MHC molecules. They differentiate into helper T-cells, cytotoxic T-cells, memory T-cells, and regulatory T-cells.
2) T-cell receptors are composed of alpha and beta chains that undergo gene rearrangement during development.
3) T-cells mature through double negative, double positive, and single positive stages in the thymus, undergoing positive and negative selection to remove self-reactive cells.
Immunogens or antigens are foreign substances that elicit an immune response when introduced to the body. They are recognized by antibodies or T-lymphocytes. Immunogens can induce antibody formation themselves, while haptens require a carrier molecule to produce an immune response. Antigens are presented on antigen-presenting cells and recognized by B and T cells, initiating humoral or cell-mediated immunity. Exogenous antigens from bacteria, viruses, and other external sources are phagocytosed and processed, while endogenous antigens from infection or autoimmunity are presented via MHC I molecules.
This document summarizes macrophage activation pathways and antimicrobial mechanisms. It discusses how macrophages are activated via classical and alternative pathways stimulated by IFN-γ/TLR agonists and IL-4/IL-13, respectively. The key antimicrobial functions of macrophages are described as phagocytosis, reactive oxygen species production, and lysosomal enzyme activity. Specific mechanisms used by pathogens to evade killing by macrophages are also reviewed.
The complement system is part of the innate immune system and consists of over 30 proteins. It was originally identified in the 1890s by Jules Bordet and Paul Ehrlich as a heat-labile component of serum that enhanced the ability of antibodies to kill bacteria. There are three complement activation pathways: the classical pathway which is initiated by antibody-antigen complexes, the lectin pathway which is activated by mannose-binding lectin, and the alternative pathway which is spontaneously activated by microbial surfaces. Complement activation results in opsonization, inflammation, and formation of the membrane attack complex to kill microbes. Deficiencies in specific complement components can increase susceptibility to certain infections.
The document provides an overview of the complement system. It discusses the history and components of the three complement pathways: the classical pathway, lectin pathway, and alternative pathway. It also describes the roles of complement components in opsonization, chemotaxis, and formation of the membrane attack complex to lyse cells. The complement system is regulated to prevent damage to host cells. Deficiencies in complement proteins can increase susceptibility to certain infections.
This document discusses cellular immune response and the roles of its key components. It describes how antigen presenting cells present antigens to T lymphocytes via MHC molecules, providing the necessary stimulatory and co-stimulatory signals for T cell activation. Activated T cells then differentiate into effector and memory T cells. Effector CD8+ T cells induce apoptosis of infected cells, while effector CD4+ T cells secrete cytokines to activate macrophages. The interactions between these immune cells are regulated by cytokines. The document also discusses antigen presentation pathways, T cell maturation in the thymus, and the roles of superantigens and cytokines in the immune response.
Immunoglobulins are antibody proteins produced by B cells that recognize and bind to antigens. They have a Y-shaped structure consisting of two heavy chains and two light chains. B cells undergo gene rearrangement processes to generate the diversity needed to recognize a wide variety of antigens. V(D)J recombination combines variable, diversity, and joining gene segments to generate the variable regions of immunoglobulins. Somatic hypermutation and class switch recombination further diversify the antibody response during infection or immune challenge. Immunoglobulins play a key role in the humoral immune response by recognizing pathogens and toxins and mediating their destruction or removal.
The complement system consists of approximately 20 proteins that are mainly synthesized by the liver and play an important role in innate immunity. It has three main effects: lysis of cells, generation of inflammatory mediators, and enhancement of phagocytosis. There are three pathways of complement activation: the classical, lectin, and alternative pathways. The classical pathway is part of acquired immunity and requires antigen-antibody complexes, while the lectin and alternative pathways are part of innate immunity and activate in response to microbial surfaces. Complement activation leads to opsonization and lysis of pathogens as well as inflammatory responses. The system is tightly regulated to prevent damage to host cells. Deficiencies in complement proteins predispose individuals to certain infections
Type I hypersensitivity reactions, also known as immediate hypersensitivity reactions, are mediated by IgE antibodies. Upon re-exposure to an allergen, IgE antibodies bound to mast cells and basophils trigger the release of inflammatory mediators such as histamine. This leads to symptoms of allergy such as sneezing, itching, and potentially life-threatening anaphylaxis. Diagnosis involves skin prick tests and measuring allergen-specific IgE levels through blood tests. Repeated allergen exposure drives the sensitization process and production of more IgE antibodies in atopic individuals.
The document summarizes the complement system, which comprises a group of serum proteins that play an important role in innate and adaptive immunity. There are three pathways of complement activation - classical, lectin, and alternative. All three pathways lead to cleavage of C3 and C5, generating factors that opsonize pathogens, recruit inflammatory cells, and directly kill pathogens. Complement activation is tightly regulated to prevent damage to host cells. Deficiencies in complement proteins can increase susceptibility to certain infections.
The document discusses the immune response, including defining immune response, the consequences and types of immune response such as humoral and cell-mediated immunity. It also covers topics like antigen processing, T cell activation, the roles of cytokines and immune cells like B cells, T cells, and antibodies in the immune response.
Primary and Secondary Immune Responses AhmedRiyadh17
The document discusses primary and secondary immune responses. The primary response occurs during first-time exposure to an antigen, when the immune system must learn to recognize and make antibodies against it. The secondary response occurs upon re-exposure, when immunological memory has been established and antibodies are produced more quickly. Key differences are that the secondary response has a shorter lag time, higher antibody levels, and antibodies with greater affinity compared to the primary response.
Chemokines are small proteins that direct the movement of white blood cells to sites of injury or infection. They are classified based on structural characteristics like the positioning of conserved cysteine residues. The four main classes are CC, CXC, C, and CX3C chemokines. Chemokines bind to G protein-coupled receptors on cells and signal through G proteins and secondary messengers to induce cell migration. Chemokines play roles in processes like inflammation, immunity, and cancer and are implicated in diseases like HIV, arthritis, and transplant rejection.
B cell Activation by T Independent & T Dependent Antigens-Dr C R MeeraMeera C R
During humoral immune response, Ab production is brought about by B lymphocytes. Based on the ability to induce Ab formation, antigens can be classified into T independent and T dependent antigens. Some antigens can directly induce the B cells to produce the Abs and are called T Independent Ans. However, some Ans require the help of T lymohocytes for the production of Abs from B cells. These Ans are called T Dependent Ans.
This document summarizes the key stages in B-lymphocyte maturation, generation, and activation. It discusses how B cells develop from progenitor cells in the bone marrow, where they undergo antigen-independent maturation including immunoglobulin gene rearrangement and positive and negative selection to remove self-reactive cells. Mature B cells then leave the bone marrow equipped with B cell receptors. The document also describes how B cells are activated upon binding of antigen to their receptor, requiring co-stimulation by T helper cells to initiate the antibody response.
The complement system is an important part of the innate immune system that activates through three pathways - classical, lectin, and alternative. Activation leads to the formation of C3 and C5 convertases that generate inflammatory molecules like C3a and C5a, and opsonins like C3b that promote phagocytosis. It ultimately forms the membrane attack complex that lyses target cells. Complement is tightly regulated to prevent damage to host cells and excessive inflammation. Deficiencies in complement components can increase risk of certain infections.
ANTIGEN, HAPTEN, ALL TYPES OF ANTIGENS, IMMUNOGEN , ATTRIBUTES OF ANTIGENICITY, DETERMINANTS OF ANTIGENICITY,
IMMUNOLOGY KUBY, MEDICAL MICROBIOLOGY & IMMUNOLOGY OF PANIKER , LIPPINCOTT'S IMMUNOLOGY, OTHER SOURCES.
The classical pathway of complement activation begins with the formation of antigen-antibody complexes that induce conformational changes in IgM or IgG antibodies, exposing a binding site for the C1 complex. C1 complex consists of C1q and C1r and C1s molecules. Binding of C1q to the antibody causes C1r to activate C1s as a protease. C1s then cleaves C4 and C2, forming the C3 convertase C4b2a that cleaves C3 into C3a and C3b. C3b binds to C4b2a to form the C5 convertase that cleaves C5, initiating formation of the membrane attack complex.
introduction of adaptive immunity. classification of adaptive immunity, factor affecting it and mechanism of adaptive immunity comparison between adaptive immunity and innate immunity. characteristic of adaptive immunity . cell mediated immune responses immunoglobulins
types of immunoglobulins. functions of immunoglobulins, hypersensitivity reactions
This document defines and discusses antigens from several perspectives:
1) It provides a brief history of the term "antigen" and its definition as a substance that stimulates antibody production.
2) It classifies antigens based on their immunogenicity as complete or incomplete antigens.
3) It categorizes antigens based on their origin as exogenous, endogenous, autoantigens, isoantigens, or heterophile antigens.
4) It lists 10 properties that determine an antigen's ability to stimulate an immune response, including foreignness, size, chemical nature, and specificity.
5) It briefly discusses superantigens and common tests used to detect antigens.
This document provides information on complement, including:
- It defines complement and describes the classical, alternative, and lectin pathways.
- Complement proteins are synthesized in the liver as inactive zymogens and are activated by proteolysis, cleaving them into larger and smaller fragments.
- The pathways differ in their initiation but then follow identical later stages, forming C3 convertase, C5 convertase, and the membrane attack complex (MAC).
- Complement has roles in targeting cell lysis, inflammation, opsonization, immune complex removal, and viral neutralization. Microorganisms have evolved mechanisms to evade complement. Regulatory proteins tightly control complement activation. Deficiencies can increase disease susceptibility
The Complement System lecture 8 chapter 8.pptxOsmanHassan35
Immunology is the study of the immune system and is a very important branch of the medical and biological sciences. The immune system protects us from infection through
Immunogens or antigens are foreign substances that elicit an immune response when introduced to the body. They are recognized by antibodies or T-lymphocytes. Immunogens can induce antibody formation themselves, while haptens require a carrier molecule to produce an immune response. Antigens are presented on antigen-presenting cells and recognized by B and T cells, initiating humoral or cell-mediated immunity. Exogenous antigens from bacteria, viruses, and other external sources are phagocytosed and processed, while endogenous antigens from infection or autoimmunity are presented via MHC I molecules.
This document summarizes macrophage activation pathways and antimicrobial mechanisms. It discusses how macrophages are activated via classical and alternative pathways stimulated by IFN-γ/TLR agonists and IL-4/IL-13, respectively. The key antimicrobial functions of macrophages are described as phagocytosis, reactive oxygen species production, and lysosomal enzyme activity. Specific mechanisms used by pathogens to evade killing by macrophages are also reviewed.
The complement system is part of the innate immune system and consists of over 30 proteins. It was originally identified in the 1890s by Jules Bordet and Paul Ehrlich as a heat-labile component of serum that enhanced the ability of antibodies to kill bacteria. There are three complement activation pathways: the classical pathway which is initiated by antibody-antigen complexes, the lectin pathway which is activated by mannose-binding lectin, and the alternative pathway which is spontaneously activated by microbial surfaces. Complement activation results in opsonization, inflammation, and formation of the membrane attack complex to kill microbes. Deficiencies in specific complement components can increase susceptibility to certain infections.
The document provides an overview of the complement system. It discusses the history and components of the three complement pathways: the classical pathway, lectin pathway, and alternative pathway. It also describes the roles of complement components in opsonization, chemotaxis, and formation of the membrane attack complex to lyse cells. The complement system is regulated to prevent damage to host cells. Deficiencies in complement proteins can increase susceptibility to certain infections.
This document discusses cellular immune response and the roles of its key components. It describes how antigen presenting cells present antigens to T lymphocytes via MHC molecules, providing the necessary stimulatory and co-stimulatory signals for T cell activation. Activated T cells then differentiate into effector and memory T cells. Effector CD8+ T cells induce apoptosis of infected cells, while effector CD4+ T cells secrete cytokines to activate macrophages. The interactions between these immune cells are regulated by cytokines. The document also discusses antigen presentation pathways, T cell maturation in the thymus, and the roles of superantigens and cytokines in the immune response.
Immunoglobulins are antibody proteins produced by B cells that recognize and bind to antigens. They have a Y-shaped structure consisting of two heavy chains and two light chains. B cells undergo gene rearrangement processes to generate the diversity needed to recognize a wide variety of antigens. V(D)J recombination combines variable, diversity, and joining gene segments to generate the variable regions of immunoglobulins. Somatic hypermutation and class switch recombination further diversify the antibody response during infection or immune challenge. Immunoglobulins play a key role in the humoral immune response by recognizing pathogens and toxins and mediating their destruction or removal.
The complement system consists of approximately 20 proteins that are mainly synthesized by the liver and play an important role in innate immunity. It has three main effects: lysis of cells, generation of inflammatory mediators, and enhancement of phagocytosis. There are three pathways of complement activation: the classical, lectin, and alternative pathways. The classical pathway is part of acquired immunity and requires antigen-antibody complexes, while the lectin and alternative pathways are part of innate immunity and activate in response to microbial surfaces. Complement activation leads to opsonization and lysis of pathogens as well as inflammatory responses. The system is tightly regulated to prevent damage to host cells. Deficiencies in complement proteins predispose individuals to certain infections
Type I hypersensitivity reactions, also known as immediate hypersensitivity reactions, are mediated by IgE antibodies. Upon re-exposure to an allergen, IgE antibodies bound to mast cells and basophils trigger the release of inflammatory mediators such as histamine. This leads to symptoms of allergy such as sneezing, itching, and potentially life-threatening anaphylaxis. Diagnosis involves skin prick tests and measuring allergen-specific IgE levels through blood tests. Repeated allergen exposure drives the sensitization process and production of more IgE antibodies in atopic individuals.
The document summarizes the complement system, which comprises a group of serum proteins that play an important role in innate and adaptive immunity. There are three pathways of complement activation - classical, lectin, and alternative. All three pathways lead to cleavage of C3 and C5, generating factors that opsonize pathogens, recruit inflammatory cells, and directly kill pathogens. Complement activation is tightly regulated to prevent damage to host cells. Deficiencies in complement proteins can increase susceptibility to certain infections.
The document discusses the immune response, including defining immune response, the consequences and types of immune response such as humoral and cell-mediated immunity. It also covers topics like antigen processing, T cell activation, the roles of cytokines and immune cells like B cells, T cells, and antibodies in the immune response.
Primary and Secondary Immune Responses AhmedRiyadh17
The document discusses primary and secondary immune responses. The primary response occurs during first-time exposure to an antigen, when the immune system must learn to recognize and make antibodies against it. The secondary response occurs upon re-exposure, when immunological memory has been established and antibodies are produced more quickly. Key differences are that the secondary response has a shorter lag time, higher antibody levels, and antibodies with greater affinity compared to the primary response.
Chemokines are small proteins that direct the movement of white blood cells to sites of injury or infection. They are classified based on structural characteristics like the positioning of conserved cysteine residues. The four main classes are CC, CXC, C, and CX3C chemokines. Chemokines bind to G protein-coupled receptors on cells and signal through G proteins and secondary messengers to induce cell migration. Chemokines play roles in processes like inflammation, immunity, and cancer and are implicated in diseases like HIV, arthritis, and transplant rejection.
B cell Activation by T Independent & T Dependent Antigens-Dr C R MeeraMeera C R
During humoral immune response, Ab production is brought about by B lymphocytes. Based on the ability to induce Ab formation, antigens can be classified into T independent and T dependent antigens. Some antigens can directly induce the B cells to produce the Abs and are called T Independent Ans. However, some Ans require the help of T lymohocytes for the production of Abs from B cells. These Ans are called T Dependent Ans.
This document summarizes the key stages in B-lymphocyte maturation, generation, and activation. It discusses how B cells develop from progenitor cells in the bone marrow, where they undergo antigen-independent maturation including immunoglobulin gene rearrangement and positive and negative selection to remove self-reactive cells. Mature B cells then leave the bone marrow equipped with B cell receptors. The document also describes how B cells are activated upon binding of antigen to their receptor, requiring co-stimulation by T helper cells to initiate the antibody response.
The complement system is an important part of the innate immune system that activates through three pathways - classical, lectin, and alternative. Activation leads to the formation of C3 and C5 convertases that generate inflammatory molecules like C3a and C5a, and opsonins like C3b that promote phagocytosis. It ultimately forms the membrane attack complex that lyses target cells. Complement is tightly regulated to prevent damage to host cells and excessive inflammation. Deficiencies in complement components can increase risk of certain infections.
ANTIGEN, HAPTEN, ALL TYPES OF ANTIGENS, IMMUNOGEN , ATTRIBUTES OF ANTIGENICITY, DETERMINANTS OF ANTIGENICITY,
IMMUNOLOGY KUBY, MEDICAL MICROBIOLOGY & IMMUNOLOGY OF PANIKER , LIPPINCOTT'S IMMUNOLOGY, OTHER SOURCES.
The classical pathway of complement activation begins with the formation of antigen-antibody complexes that induce conformational changes in IgM or IgG antibodies, exposing a binding site for the C1 complex. C1 complex consists of C1q and C1r and C1s molecules. Binding of C1q to the antibody causes C1r to activate C1s as a protease. C1s then cleaves C4 and C2, forming the C3 convertase C4b2a that cleaves C3 into C3a and C3b. C3b binds to C4b2a to form the C5 convertase that cleaves C5, initiating formation of the membrane attack complex.
introduction of adaptive immunity. classification of adaptive immunity, factor affecting it and mechanism of adaptive immunity comparison between adaptive immunity and innate immunity. characteristic of adaptive immunity . cell mediated immune responses immunoglobulins
types of immunoglobulins. functions of immunoglobulins, hypersensitivity reactions
This document defines and discusses antigens from several perspectives:
1) It provides a brief history of the term "antigen" and its definition as a substance that stimulates antibody production.
2) It classifies antigens based on their immunogenicity as complete or incomplete antigens.
3) It categorizes antigens based on their origin as exogenous, endogenous, autoantigens, isoantigens, or heterophile antigens.
4) It lists 10 properties that determine an antigen's ability to stimulate an immune response, including foreignness, size, chemical nature, and specificity.
5) It briefly discusses superantigens and common tests used to detect antigens.
This document provides information on complement, including:
- It defines complement and describes the classical, alternative, and lectin pathways.
- Complement proteins are synthesized in the liver as inactive zymogens and are activated by proteolysis, cleaving them into larger and smaller fragments.
- The pathways differ in their initiation but then follow identical later stages, forming C3 convertase, C5 convertase, and the membrane attack complex (MAC).
- Complement has roles in targeting cell lysis, inflammation, opsonization, immune complex removal, and viral neutralization. Microorganisms have evolved mechanisms to evade complement. Regulatory proteins tightly control complement activation. Deficiencies can increase disease susceptibility
The Complement System lecture 8 chapter 8.pptxOsmanHassan35
Immunology is the study of the immune system and is a very important branch of the medical and biological sciences. The immune system protects us from infection through
This document provides an overview of the complement system submitted by five MSc students to their professor. It describes that complement was first discovered in 1890 and plays a major role in innate immunity through lysis of cells, opsonization, and inflammation. It summarizes the three pathways of complement activation (classical, lectin, and alternative), components and regulation of the complement system, and consequences of complement activation including cell lysis, inflammation, opsonization, viral neutralization, and solubilization of immune complexes.
The document summarizes the complement system. It discusses the three complement pathways - classical, alternative, and lectin pathways. It also describes the structure and function of the membrane attack complex (MAC), which forms pores in pathogen cell membranes leading to lysis. The complement system plays an important role in innate immunity by opsonizing pathogens, attracting immune cells, and directly lysing certain pathogens.
Innate immunity is the body's first line of defense against pathogens. It includes mechanical, chemical, and biological barriers that block pathogen entry. If a pathogen breaches these barriers, the innate immune system responds through cells and proteins. Key components of the innate response are phagocytic cells, complement proteins, acute phase proteins, cytokines, and inflammation. The complement system helps eliminate pathogens through opsonization, cell lysis, and inflammation. Innate immunity provides non-specific protection and helps activate the adaptive immune response.
Complement system and innate immunity - classical & alternative pathways neeru02
The complement system is part of the innate immune system that enhances the ability of antibodies and phagocytes to clear pathogens. It consists of around 20 proteins that are activated via three pathways: the classical pathway activated by antigen-antibody complexes, the lectin pathway activated by lectins binding to pathogens, and the alternative pathway which is continuously active at low levels. Complement activation leads to the formation of the membrane attack complex that forms pores in pathogen cell membranes to kill them directly or mark them for phagocytosis.
The complement system is a group of proteins in the blood that helps antibodies and phagocytic cells destroy pathogens. It is activated via three pathways - classical, lectin, and alternative. Activation leads to a cascade of reactions that results in the formation of the membrane attack complex, which punches holes in the pathogen's cell membrane, killing it. Complement also aids in inflammation, phagocytosis, and immune adherence. The system is tightly regulated to prevent damage to host cells. Deficiencies can cause diseases like hereditary angioedema.
The document provides an overview of the complement system in fish. It discusses:
1) The complement system consists of soluble and membrane-bound proteins that play a critical role in the host defense through interactions with both the innate and adaptive immune systems.
2) The complement system has three pathways - classical, lectin, and alternative - that recognize pathogens and promote their clearance through lysis, opsonization, and inflammation.
3) Complement components are produced as inactive zymogens and activated through proteolytic cleavage in cascading reactions on pathogen surfaces to form the membrane attack complex, which lyses cells.
This presentation describes the Fish Complement system and different types of pathways involved and the mechanism behind the regulation of complement proteins. It gives a basic and a detailed explanation regarding the topic.
The document discusses the complement system, which consists of three pathways - the classical, alternative, and lectin pathways. When activated via one of these pathways, complement proteins are activated in a cascade pattern, forming complexes that opsonize pathogens, enhance inflammation and antibody responses, and directly attack pathogens. The membrane attack complex is the final product of complement activation, forming pores in pathogen membranes that cause lysis.
Adaptive immunity is induced in response to specific antigens after collaboration between phagocytic cells, T and B lymphocytes, and production of immunoglobulins and lymphokines. There are two types of adaptive immunity: humoral immunity mediated by secreted antibodies and cell-mediated immunity which activates phagocytes, natural killer cells, cytotoxic T-lymphocytes and cytokines without antibodies. Humoral immunity involves B cell transformation into plasma cells secreting antibodies, while cell-mediated immunity blocks intracellular microbes by activating macrophages or cytotoxic T cells killing infected cells.
The complement system consists of serum proteins that work together to help clear pathogens from the body. It activates through three pathways: the classical pathway which is activated by antibody-antigen complexes, the lectin pathway which is activated by mannose-binding proteins binding pathogens, and the alternative pathway which is activated by pathogen surfaces. Complement activation leads to the formation of complexes that can lyse cells, promote inflammation, opsonize pathogens to mark them for phagocytosis, and clear immune complexes and apoptotic cells from the body.
There are three pathways of complement activation: the classical pathway, which is triggered directly by pathogen or indirectly by antibody binding to the pathogen surface; the MB-lectin pathway; and the alternative pathway, which also provides an amplification loop for the other two pathways
The document discusses the complement system, which consists of over 20 proteins that play a key role in the immune system. There are three complement activation pathways: the classical pathway, which is initiated by the binding of antibodies to antigens; the lectin pathway, which is initiated when mannose-binding lectin binds to pathogens; and the alternative pathway, which is spontaneously activated by pathogens. All three pathways result in the formation of the membrane attack complex that causes lysis of pathogens. The complement system enhances phagocytosis, causes inflammation, and lyses cells through its activation cascade and production of factors such as C3a and C5a.
Immunology is the study of the immune system and is a very important branch of the medical and biological sciences. The immune system protects us from infection through
The complement system consists of over 20 proteins that are part of the innate and adaptive immune system. There are three pathways of complement activation - the classical, lectin, and alternative pathways. All three pathways result in the formation of the membrane attack complex that causes cell lysis. The complement system functions to opsonize pathogens, induce inflammation, clear immune complexes, and lyse cells. It is tightly regulated to prevent damage to host cells. Deficiencies in specific complement proteins can increase susceptibility to certain pathogens.
Complement system and its synthesis + activationVaisHali822687
Proteins normally found in serum in inactive form, but when activated they augment the immune responses.
Complements constitute about 5% of normal serum proteins.
Their level does not increase following either infection or vaccination.
There are four main stages in the activation of any of the complement pathways.
Initiation of the pathway
Formation of C3 convertase
Formation of C5 convertase
Formation of membrane attack complex (MAC)
Complement System comprises of Complement proteins that function to augment the antibodies in killing bacteria by the formation of Membrane Attack Complex.
This ppt describes the different pathways of activation complement proteins and MAC formation.
Resistant hypertension is defined as blood pressure that remains above goal despite concurrent use of three antihypertensive agents of different classes, one of which should be a diuretic. It has a prevalence of 0.5-24.7% depending on the population. Causes include nonadherence, lifestyle factors like obesity and sleep apnea, secondary causes like primary aldosteronism and renal artery stenosis, and drug interactions. Evaluation involves assessing medication adherence, lifestyle behaviors, screening for secondary causes with tests like the aldosterone-renin ratio, and imaging of the kidneys and arteries. Management consists of optimizing lifestyle modifications, adjusting medications like adding mineralocorticoid receptor antagonists, and treating any identified
Dr. Prem Mohan Jha presented on mycophenolate mofetil (MMF) and azathioprine, two immunosuppressive medications used in kidney transplant recipients. MMF is an prodrug of mycophenolic acid that is absorbed and converted in the liver. It is generally well tolerated though can cause gastrointestinal side effects. While azathioprine is older and less used now, both work by inhibiting purine synthesis and interfering with RNA and DNA synthesis to prevent rejection. Monitoring is important due to potential adverse effects like leukopenia.
Multiple myeloma is a cancer of plasma cells that produce abnormal antibodies. When myeloma cells spread throughout the bone marrow, it is called multiple myeloma. Renal impairment is a common feature of symptomatic multiple myeloma and can provide a clue to the diagnosis. The International Myeloma Working Group diagnostic criteria require either 10% or more plasma cells in the bone marrow or a biopsy-proven plasmacytoma plus evidence of end organ damage like hypercalcemia, renal insufficiency, anemia, or bone lesions.
1) Sirolimus is an immunosuppressant that was first investigated as an antifungal agent in the 1970s and was found to have immunosuppressive properties in 1971. It was approved by the FDA for immunosuppression in 1999.
2) Sirolimus works by binding to FKBP and inhibiting the mTOR pathway, which leads to inhibition of lymphocyte proliferation. This results in reduced T and B cell proliferation.
3) Therapeutic drug monitoring is recommended for sirolimus and everolimus, as trough levels correlate well with efficacy and toxicity. The target trough range is generally 5-15 ng/mL for sirolimus and 3-8 ng/mL for ever
This document discusses hypertensive disorders of pregnancy including gestational hypertension, preeclampsia, eclampsia, and HELLP syndrome. Key points:
1. Preeclampsia affects 10-12% of pregnancies and is a leading cause of maternal death worldwide. It involves new onset hypertension and proteinuria after 20 weeks.
2. Diagnosis, monitoring, and management involves frequent blood pressure monitoring, urine and blood tests. Delivery is usually indicated for worsening conditions or after 37 weeks.
3. Magnesium sulfate is used for seizure prophylaxis in preeclampsia patients and blood pressure control is important for reducing maternal risks while allowing further fetal growth.
The document provides information on the functional anatomy of the glomerulus and tubules in the kidney. It discusses the development of the kidney from the intermediate mesoderm. It describes the gross features and internal anatomy of the kidney including the cortex, medulla, calyces, and pelvis. It details the microanatomy of the nephron including the glomerulus, Bowman's capsule, blood supply, tubular segments like the proximal and distal tubules, and the loop of Henle. It explains the specialized cell types in the nephron like podocytes, mesangial cells and their roles. It also discusses the juxtaglomerular apparatus and its role in regulating blood pressure and filtrate
This document summarizes a randomized controlled trial comparing rituximab to cyclophosphamide for inducing remission in patients with severe ANCA-associated vasculitis. The trial found rituximab to be non-inferior to cyclophosphamide at inducing remission at 6 months when both were combined with glucocorticoids. Rituximab achieved similar rates of remission and disease control as cyclophosphamide with comparable safety profiles. Based on these results, rituximab was subsequently approved by the FDA for treatment of granulomatosis with polyangiitis and microscopic polyangiitis.
This document discusses erythropoietin (EPO) and anemia. It contains the following key points:
1. EPO is a glycoprotein hormone produced mainly by the kidneys that stimulates red blood cell production. Recombinant human EPO (rHuEPO) was developed with the same polypeptide backbone but differences in glycosylation compared to natural EPO.
2. Later generation ESAs like darbepoetin alfa have a longer half-life, allowing less frequent dosing. PEGylated ESAs like CERA have an even longer half-life of 130 hours, permitting monthly dosing.
3. Other experimental ESAs include those with fused
This document presents a case report of a 54-year-old diabetic male who presented with bilateral emphysematous pyelonephritis (EPN), a rare and life-threatening infection involving gas in the renal parenchyma. Despite initial treatment with antibiotics, the patient deteriorated and developed multiple organ dysfunction. Imaging revealed extensive EPN. Due to the patient's critical condition, nephrectomy was not pursued. He was managed medically with prolonged antibiotics and supportive care. After 4 weeks, follow up imaging showed no significant changes but the patient remained dependent on hemodialysis. The document then reviews EPN including causes, presentation, diagnosis, staging, and management approaches.
This document summarizes guidelines for evaluating kidney function in potential living donors. It recommends estimating glomerular filtration rate (GFR) using serum creatinine and/or cystatin C to assess kidney function. An initial GFR of 90 mL/min/1.73m2 or greater is acceptable for donation, while GFR between 60-89 mL/min/1.73m2 requires individual assessment. Donors with less than 60 mL/min/1.73m2 are not eligible. The guidelines provide criteria for measurement and interpretation of GFR to safely evaluate and select living kidney donors.
This document discusses guidelines for prescribing hemodialysis for acute kidney injury patients. It covers key elements of the prescription including session length and blood flow rate, dialyzer selection, dialysate composition, and ultrafiltration orders. The presentation emphasizes starting more frequent but shorter sessions at lower intensity initially and gradually increasing session length and clearance as the patient stabilizes to prevent dialysis disequilibrium syndrome.
This document discusses maintenance immunosuppressive therapy for kidney transplant recipients. It provides details on tacrolimus and cyclosporine, including their mechanisms of action, dosing, therapeutic drug monitoring, and conversion between formulations. Adverse effects and contraindications are also summarized. Monitoring drug levels is important for efficacy and toxicity, with target trough ranges outlined for different time periods post-transplant.
Therapeutic plasma exchange (TPE) is an extracorporeal blood purification technique used to remove large molecular weight substances from the plasma, such as pathogenic autoantibodies, immune complexes, and myeloma light chains. There are two main methods for TPE - centrifugal plasma separation and membrane plasma separation. TPE aims to remove the target pathogenic substance by exchanging 1-1.5 plasma volumes in each procedure to allow for redistribution between plasma and tissues. Complications are generally minor but can include hypotension, allergic reactions, and in rare cases mortality. TPE has various indications like myasthenia gravis, Guillain-Barré syndrome, and cryoglobulinemia where removal of
This study developed and validated a preoperative acute kidney injury (PO-AKI) risk prediction index called SPARK for noncardiac surgeries. Using data from two Korean hospitals, the study identified preoperative risk factors to stratify patients into four risk classes (A to D). Class A patients had the lowest PO-AKI risk while class D the highest. The simple index uses only preoperative variables and can help clinicians decide which patients need PO-AKI monitoring after surgery. While not perfect, the SPARK index provides a practical tool to predict and prevent PO-AKI.
This document summarizes results from the AURA-LV clinical trial studying the efficacy and safety of voclosporin in treating lupus nephritis. The trial found that patients receiving 23.7 mg of voclosporin twice daily were over twice as likely to achieve complete renal remission at 24 weeks compared to the placebo group. They were also more likely to achieve partial remission and saw faster time to response. At 48 weeks, the low-dose voclosporin group maintained higher remission rates and saw continued improvement in proteinuria levels over time, demonstrating voclosporin's potential as a new treatment for lupus nephritis.
The document summarizes three landmark clinical trials (CREATE, CHOIR, TREAT) that studied the use of erythropoietin (EPO) for treating anemia in chronic kidney disease (CKD) patients.
The CHOIR trial found that aiming for a higher hemoglobin target (13.5 g/dL) compared to a lower target (11.3 g/dL) increased risks of cardiovascular events and hospitalization. The CREATE trial found no benefit to early anemia treatment to reach a hemoglobin of 13.5 g/dL compared to 11.6 g/dL. The TREAT trial found darbepoetin alfa reduced transfusion needs but increased risks of strokes with no benefit on
This document summarizes the Study Of Diabetic Nephropathy With AtraSentan (SONAR) trial. The trial aimed to assess the efficacy and safety of the selective endothelin receptor antagonist Atrasentan in patients with type 2 diabetes and chronic kidney disease. Over 5,000 patients were screened and 2,648 responders were randomly assigned to Atrasentan or placebo. The primary outcome was a composite of doubling of serum creatinine, end stage renal disease, or death from kidney failure. The trial found that Atrasentan reduced the risk of the primary composite renal outcome compared to placebo but was associated with more adverse events like fluid retention and anemia.
Dr. Prem Mohan Jha discussed the need for pure water in dialysis and the water purification system used to provide it. Two main water sources are surface and groundwater, both of which can contain various contaminants harmful for dialysis patients. The water purification system uses multiple steps including carbon filtration, softening, reverse osmosis, and sometimes deionization to remove contaminants. Strict water quality standards must be followed and the various components of the system such as softeners and filters require regular monitoring, maintenance and disinfection to ensure water purity and prevent bacterial growth.
Echocardiography uses ultrasound technology to produce images of the heart. It was pioneered in the 1950s by Drs. Hertz and Edler in Sweden using an ultrasonoscope originally developed for non-destructive testing. Modern echocardiography machines generate ultrasound images using a transducer that transmits sound waves into the body and receives echoes to produce cardiac images. Standard echocardiograms visualize the heart in 2D, M-Mode, and with Doppler modalities from different transducer positions. Echocardiography is used to assess cardiac structure and function, valve abnormalities, wall motion, blood flow, and the presence of pericardial fluid or masses. It provides diagnostic and prognostic information for many cardiac
This document provides an overview of acute kidney injury (AKI) in pregnancy. It discusses the definition of AKI in pregnancy, epidemiology, physiologic changes during pregnancy that impact the kidneys, common etiologies of AKI including preeclampsia, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome. It also covers the diagnostic approach, differential diagnosis, and treatment considerations for AKI in pregnancy.
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These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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We’re talking about Vedic Meditation, a form of meditation that has been around for at least 5,000 years. Back then, the people who lived in the Indus Valley, now known as India and Pakistan, practised meditation as a fundamental part of daily life. This knowledge that has given us yoga and Ayurveda, was known as Veda, hence the name Vedic. And though there are some written records, the practice has been passed down verbally from generation to generation.
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Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
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There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
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Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
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2. COMPLEMENT
Definition
A system of factors that occur in normal serum and
are activated characteristically by antigen ‐
antibody interaction and subsequently mediate a
number of biologically significant consequences.
3. COMPLEMENT SYSTEM
• Major effector of humoral branch of immune system.
• Biochemical cascade that helps or “complements” the ability
of antibodies to clear pathogens from an organism.
• Part of innate immune system.
• However, can be recruited and brought into action by the
adaptive immune system.
4.
5. HISTORY
• 1889‐ Hans Ernst Buchner, first observed that bactericidal
effect of the serum was destroyed by heating at 55o C for one
hour.
• 1894‐ Pfieffer discovered that cholera vibrios were lysed when
injected intraperitoneally into specifically immunized guinea
pigs (bacteriolysis in vivo or Pfieffer’s phenomenon).
6. HISTORY
• 1895‐ Joules Bordet established that immune bacteriolysis
and hemolysis required two factors‐ heat stable antibody and
a heat labile factor, k/a alexine.
• Later on, Ehrlich coined the term complement because this
factor complemented the action of the antibody.
• 1901‐ Bordet and Gengou, described the complement
fixation test, using the hemolytic indicator system, as a
sensitive serological reaction.
7. FUNCTIONS OF THE COMPLEMENT
1. Lysis of cells, bacteria and viruses.
2. Opsonization, which promotes phagocytosis of particulate
antigens.
3. Binding to specific complement receptors on cells of the immune
system, triggering specific cell functions, inflammation, and
secretion of immunoregulatory molecules.
4. Immune Clearance, which removes immune complexes from
immune system and deposits them in the spleen and liver.
8.
9. GENERAL PROPERTIES
• Present in sera of all mammals and also in most other
animals, including birds, amphibians and fish.
• Nonspecific serological reagent‐ complement from one
species can react with antibodies of other species.
• Soluble proteins and glycoproteins
• Synthesized mainly by liver hepatocytes, also by blood
monocytes, tissue macrophages and epithelial cells of GIT and
GUT.
10. • 5 % of normal serum proteins, not increased by
immunization.
• Heat labile; destroyed in 30 mins at 56o C.
• Inactivated serum‐ serum deprived of
complement activity.
• Present as ‘Zymogens’ or inactive forms(denoted by ‘i’) in
circulation and are activated by proteolytic cleavage.
12. COMPLEMENT‐COMPONENTS
Molecular weight Serum concentration(μg/ml)
Alternative pathway component
Properdin 53,000 25
Factor B 90,000 225
Factor D 25,000 1
Inhibitors
C1 inhibitor 105,000 275
Factor I 88,000 34
Regulatory proteins
C4‐binding protein 560,000 8
Factor H 150,000 500
S protein (vitronectin) 80,000 500
13. COMPLEMENT‐ COMPONENTS
• Components‐ designated by numerals (C1‐C9), letter
symbols (e.g. factor D) or trivial names (homologous
restriction factor).
• Larger fragment is designated as ‘b’ and smaller
fragment as ‘a’ except C2a (larger fragment).
• Larger fragment participates in cascade while
smaller fragment diffuses away.
• Activated form is denoted by a bar over the
number or symbol e.g. C¯4b.
14. COMPLEMENT PATHWAYS
• Early steps culminating in formation of C5 convertase, can
occur by:
a) Classical pathway,
b) Alternative pathway, or
c) Lectin pathway.
• Final steps leading to formation of MAC are identical in all
three pathways.
15. STRUCTURE OF C1
• Initiator of cascade in classical complement pathway.
• Macromolecular complex composed of 3 different proteins(C1q,
C1r and C1s) held together by Calcium ions.
• Each C1 complex composed of one C1q, 2 C1r and 2 C1s chains.
• Enzymatic potential resides in C1r and C1s.
• C1q complex is itself composed of 6 identical subunits each
carrying 3 different polypeptide chains forming triple helical
structure.
16. STRUCTURE OF C1
• 6 subunits are arranged to form a globular central core from
which 6 arms radiate outward.
• At the end of each arm is a podlike hand that is formed by
carboxy termini of all 3 chains and mediates binding to Fc
piece (CH 2 domains of IgG and CH 4 of IgM) of
immunoglobulins of appropriate subclasses.
• C1q binds to IgM, IgG3, IgG1 and IgG2 but not IgG4, IgA and
IgE.
17.
18. CLASSICAL PATHWAY
• Triggered by formation of Ag‐Ab complex.
• Non-immunologic pathway activators‐
– Certain bacteria and viruses,
– Surface of urate crystals,
– Myelin basic protein,
– Denatured DNA,
– Bacterial endotoxin and
– Polyanions such as heparin.
19. CLASSICAL PATHWAY
• C1q binds antigen bound antibody.
• C1r activates auto catalytically and activates the second C1r;
both activate C1s.
• C1s cleaves C4 and C2. Cleaving C4 exposes the binding site
for C2.
• C4b binds the surface near C1 and C2 binds C4, forming C3
convertase.
20. CLASSICAL PATHWAY
• C3 convertase hydrolyzes many C3 molecules. Some combine
with C3 convertase to form C5 convertase.
• C3b component of C5 convertase binds C5, permitting
C¯4b2a to cleave C5.
• C5b binds C6, initiating the formation of the membrane
attack complex.
21.
22.
23. ALTERNATIVE PATHWAY
• No antigen antibody complexes required for initiation.
• Component of innate immune system.
Four serum proteins are required:
1. C3
2. Factor B
3. Factor D
4. Properdin
24. INITIATORS OF ALTERNATIVE PATHWAY
Pathogens and particles of microbial origin Non pathogens
Many strains of gram negative bacteria Human IgG, IgA, and IgE complexes
LPS from gram negative bacteria Rabbit and guinea pig IgG in complexes
Many strains of gram positive bacteria Cobra venom factor
Teichoic acid from gram positive cell walls Heterologous erythrocytes (rabbit, mouse,
chicken)
Fungal and yeast cells (zymosan) Anionic polymers (dextran sulfate)
Some viruses and virus infected cells Pure carbohydrates (agarose, inulin)
Some tumor cells
Parasites (trypanosomes)
25. ALTERNATIVE PATHWAY
• C3 hydrolyzes spontaneously to form C3(H2O) which in
presence of Mg ions bind Factor B, and further acted on by
Factor D to cleave Factor B forming a complex having C3
convertase (C3bBb) activity.
• Binding of Properdin stabilizes C3 convertase, slowing its
decay.
• C3 convertase further cleave additional C3 to form C3B and
form larger complex C3BBB3B k/a C5 convertase.
• C5b binds to antigenic surface commencing final phase of lytic
cycle.
26.
27. LECTIN PATHWAY (MBL ‐ MASP)
• Lectins are proteins that bind to specific
carbohydrate targets.
• Lectin activating complement binds to mannose residues;
present on surface of various bacterial cells, fungi and
viruses, so also called as MBL (mannan‐binding lectin
pathway)
• Human cells have sialic acid residues covering sugar groups
hence are not the target for binding.
• Lectin pathway is homologous to classical pathway but not
activated by antibodies like alternate pathway.
28. LECTIN PATHWAY (MBL ‐ MASP)
• MBL‐ acute phase protein; conc. increases during
inflammation.
• Similar in structure and function to C1q.
• After MBL bind to carbohydrate, MBL associated serine
proteases, MASP‐1 and MASP‐2 bind to MBL.
• This active complex causes cleavage of C4 and C2 forming
C3 and then C5 convertase.
29.
30. FORMATION OF MAC
• Terminal sequence of complement activation involves C5b, C6,
C7, C8 and C9, which interact sequentially to form a
macromolecular structure called the membrane attack
complex.
• It forms a large channel through the membrane of the
target cell, enabling ions and small molecules to diffuse
freely across the membrane.
31. FORMATION OF MAC
• C5b formed by C5 convertase is rapidly inactivated unless
stabilized by C6 next component in the cascade.
• C5b6 complex binds C7 to form strongly hydrophobic molecule
i.e. C5b67 which is capable of inserting itself into the lipid
bilayer of cell membranes.
32. FORMATION OF MAC
• This complex accepts one molecule of C8 and multiple
molecules of C9 to ultimately form a ‘cylindrical
transmembrane channel’ termed as membrane attack
complex (MAC).
• MAC has outer hydrophobic surface and inner hydrophilic
core through which small ions and water can pass.
• Water enters cell because of high osmotic pressure inside
the cell and the cell swells and bursts.
33.
34.
35. REGULATION OF COMPLEMENT PATHWAY
• The complement system has the potential to be extremely
damaging to host tissues, hence regulatory mechanisms are
required to restrict the complement pathway.
o Passive mechanism: highly labile components that
undergo spontaneous inactivation if not stabilized by
other components.
o Active mechanism: series of regulatory proteins that
inactivate various complement components.
36. REGULATION OF COMPLEMENT PATHWAY
• Present at a higher concentration in the blood plasma than
the complement proteins and also on the membranes of
self‐cells preventing them from being targeted by
complement e.g. CD59
• Reaction catalyzed by C3 convertase is the major amplification
step in 3 pathways generating hundreds of C3b molecules.
• Many regulatory proteins check the activity of C3
convertase.
37. REGULATION OF COMPLEMENT PATHWAY
• These regulatory proteins(DAF, Factor H, C4BP, CR1 and CR2)
contain repeating amino acid sequences of about 60 residues
termed short consensus repeats (SCRs) and are encoded at a
single location on Chr. 1 in humans k/a regulators of
complement activation(RCA) gene cluster.
• Genes for C4, C2 and Factor B are located on short arm of Chr.
6 in humans and are termed as class III histocompatibility
genes.
38. REGULATORY PROTEINS
Protein Type of protein Pathway affected Immunologic function
C1 inhibitor(C1Inh) Soluble Classical Serine protease inhibitor;
causes C1r2s2 to dissociate
from C1q
Also an inhibitor of activated
Hageman factor
C4b‐binding
protein(C4Bp)
Soluble Classical and lectin Blocks formation of C3
convertase by binding C4b;
cofactor for cleavage of C4b by
factor I
Factor H Soluble Alternative Blocks formation of C3
convertase by binding C3b;
cofactor for cleavage of C3b by
factor I
39. Protein Type of protein Pathway affected Immunologic function
Factor I Soluble Classical, alternative Serine protease:
and lectin cleaves C4b or C3b
using C4bBP, CR1,
factor H, DAE, or MCP
as cofactor
S protein/ Soluble Terminal Binds soluble C5b67
Vitronectin and prevents its
insertion into cell
membrane
Anaphylatoxin Soluble Effector Inactivates
inactivator anaphylatoxin activity
of C3a and C5a by
carboxypeptidase N‐
catalyzed removal of C‐
terminal Arginine.
40. Protein Type of protein Pathway affected Immunologic function
Decay‐accelerating
factor (DAF or CD35)
Membrane
bound
Classical, alternative
and lectin
Accelerates dissociation of
C¯¯¯4b2a and C¯3bBb(classical
and alternative C3
convertases)
Homologous
restriction factor
(HRF)
Membrane
bound
Terminal Bind to C5b678 on
autologous cells, blocking
binding of C9
CD59 Membrane
bound
Terminal Bind to C5b678 on
autologous cells, blocking
binding of C9
Complement
receptor type 1(CR1
or CD35) Membrane‐
cofactor protein
(MCP or CD46)
Membrane
bound
Classical, alternative
and lectin
Blocks formation of C3
convertase by binding C4b
or C3b; cofactor for factor I‐
catalyzed cleavage of C4b or
C3b
41. COMPLEMENT RECEPTORS(CR)
• Many of the biological activities of the complement
system depend on binding of complement fragments
to complement receptors, expressed by various cells.
• Some complement also play an important role in regulating
complement activity by binding biologically active
complement components.
46. EVASION MECHANISMS BY VIRUSES
• Interference with the binding of complement to
antigen‐antibody complexes e.g. Herpes virus
• Viral mimicry of mammalian complement regulators
e.g. Vaccinia virus
• Incorporation of cellular complement regulators in the virion
e.g. HTLV‐1.
47. EVASION MECHANISM BY HELMINTHS
• Helminths usually evade the effects of complement by
inhibiting complement action or increased local consumption
of complement factors.
• In Schistosomes, following mechanisms are there‐
i. Secretion of muscle protein ‘paramyosin’‐ bind C1q and
inhibit binding of C4; prevent complement activation.
ii. Lipid anchored protease on surface of larva‐ cleave C3
and C9; inhibit complement mediated and neutrophil
dependent killing.
48. EVASION MECHANISM BY HELMINTHS
Protease inhibitor (similar to CD59)‐ blocks assembly
of MAC.
– Incorporation of DAF in outer surface membrane of cyst
wall*.
• In Echinococcus granulosus, Factor H gets
incorporated into cyst wall*.
*‐‐ DAF and Factor H inhibit the activation of
complement cascade downstream of C3bBb
complex.
• In Taenia taeniaeformis, early complement factors get
stick to the mucopolysaccharide in cystic bladder fluids.
49. COMPLEMENT SYSTEM ASSOCIATED DISEASES
3 Groups of diseases that result from abnormality
of complement system:
1. Deficiency of some component of complement
system
2. Abnormalities of regulation of complement system
3. Stimulation of complement system by abnormal
stimuli.
51. COMPLEMENT DEFICIENCIES
• Deficiency of early components like C3, C2and C4.
• Terminal complex component deficiency i.e. C5‐C9 resulting
in lack of MAC complex.
• Abnormalities of regulatory proteins
52. COMPLEMENT DEFICIENCY DISEASES
Complement deficiency Disease/pathology
A Classical pathway deficiency
C1q, C1r, C1s SLE with pyogenic infections
C4 SLE with glomerulonephritis
C2 SLE , vasculitis, glomerulonephritis and
pyogenic infection
B Alternative pathway deficiency
Properdin Neisserial infections and pyogenic
infections
Factor D
C Common deficiencies in both pathways
C3 Immune complex disease, pyogenic
infections and glomerulonephritis
D Terminal component deficiency
C5, C6, C7, C8 Disseminated Neisserial infections
C9 None
53. COMPLEMENT REGULATORY PROTEIN DISEASES
Protein Complement abnormality Disease/ pathology
C1 inhibitor (C1 inh) Overactive classical pathway Hereditary angioneurotic
oedema
DAF and CD 59 Deregulated C3 convertase
activity‐ increased RBC lysis
Paroxysmalnocturnal
hemoglobulinuria
Factor I Deregulated classical
pathway with
overconsumption of C3
Immune complex disease;
recurrent pyogenic infections
Factor H Deregulated alternative
pathway with increased C3
convertase activity
Immune complex disease
and pyogenic infections
54. ABNORMALITIES ARISING FROM NORMAL
COMPLEMENT SYSTEM
• Bystander damage of the normal cells: damage of cells in the
immediate vicinity of the released inflammatory mediators
e.g. free radicles, histamine etc.
• Intravascular thrombosis leading to ischemic effects due to
following possible reasons:
i. Damaged endothelial surface following complement
activation favours thrombosis.
ii. Pre‐ cytolytic MAC complexes‐ cause activation of
prothrombinases.
• C5a may alter endothelial surface heparan sulphate
promoting coagulation.
55. ROLE OF COMPLIMENTS IN HYPERSENSITIVITY
REACTIONS
• Role in type II and type III hypersensitivity reactions.
Type II Reaction: mediated by IgG or IgM to foreign
antigens which are bound to cell surfaces or other
molecules.
Type III reaction:
Due to excessive formation of immune complex (Ag‐Ab
complex).
o Localized reaction: e.g. Arthus reaction.
o Generalized reaction : e.g. Serum sickness.
56. COMPLEMENT THERAPIES
• Breakthrough came in early 1990s, when it was demonstrated
that an engineered recombinant soluble form of a natural C
regulator, CR1, was powerful inhibitor of C activation both in
vitro and vivo.
• Considerations:
i. Side effects of long term systemic inhibition of C
synthesis.
ii. Choice of most efficient point at which to inhibit the
complement.
iii. Rapid clearance of reagents in vivo.
iv. High cost of biological therapies.
57. COMPLEMENT THERAPIES
Agent History and status Pros Cons
sCR1 (TP10) The first of the new
generation of anti‐C
therapies; used in many
models; first in clinical
trials. Now superseeded?
Proof of concept; works
across species
Expensive
Systemic
Sle‐sCR1 (TP20) First of the modified
sCR1 agents; binds
endothelium at sites of
inflammation, tested in
many models, no clinical
trial.
May be more ‘site specific’
than sCR1
Expensive
Systemic
APT‐070 Truncated, membrane‐
targeted sCR1 derivative,
tested in several models,
early stages of clinical
trials.
‘Site specific’ ?, retained
at injection site? Made in
bacteria so cheaper?
Unproven
Systemic
58. COMPLEMENT THERAPIES
Agent History and status Pros Cons
h5G1.1 and
derivatives
Recombinant scFv of
anti‐C5 monoclonal
antibody (mAb); permits
opsonization; effective
in several models; well
advanced in clinical trials
Long term half life
compared with sCR1;
relatively cheap; nearest to
the clinic. The mAb‐based
therapies well accepted
Systemic
C5aR antagonists Several agents vying for
this niche; attractive
drug target; many
positive results in
models.
Small molecule agents
(peptides and others); may
be inexpensive, may work
orally or topically
Unproven
Small molecule
antagonists of
components
Numerous agents, best
explored is the C3
inhibitor Compstatin;
good results in models,
no trials
May be inexpensive, may
be active orally or topically
Unproven
59. COMPLEMENT FIXATION TEST
• Complement takes part in many immunological reactions
and is absorbed during the combination of antigens with
their antibodies.
• The ability of antigen‐antibody complexes to ‘fix’ complement
is made use of in the complement fixation test (CFT).
• Very versatile and sensitive test, capable of detecting as
little as 0.04mg of antibody and 0.1ml of antigen.
60. COMPLEMENT FIXATION TEST
• CFT‐ complex procedure consisting of two steps and five
reagents‐ Antigen, Antibody, Complement, Sheep erythrocytes
and Amboceptor (Rabbit antibody to sheep red cells).
• Each of these agents have to be separately standardized.
61.
62. CFT
• Antigen: soluble/particulate
• Antibody: heat inactivated serum used to destroy complement
activity and nonspecific inhibitors of complement
• Source of complement: guinea pig serum
• Indicator system: sheep erythrocytes with amboceptor
• Diluent used for titrations and for CFT‐ physiological saline
with added calcium and magnesium ions.
63. CFT
• Guinea pig serum should be titrated for activity.
• One unit or MHD of complement is defined as the highest
dilution of the guinea pig serum that lyses one unit volume of
washed sheep erythrocytes in the presence of excess
hemolysin (amboceptor) within fixed time (usually 30 or 60
minutes) at a fixed temperature (37o C).
64. CFT
• Amboceptor should be titrated for hemolytic activity.
• One MHD of amboceptor is defined as the least amount (or
highest dilution) of the inactivated amboceptor that lyses one
unit volume of washed sheep erythrocytes in the presence of
excess complement within a fixed time (usually 30 or 60
minutes) at a fixed temperature (37o C).
65. CFT
• Adequate controls should be used; like
1. Antigen and serum controls to ensure that they are not
anticomplementary
2. Complement control to ensure that the desired amount
of complement is added
3. Cell control to see that sensitised erythrocytes do not
undergo lysis in the absence of complement.
66.
67. CFT
• Classical example of CFT: Wassermann reaction
• Indirect complement fixation test: used for certain avian and
mammalian sera not fixed by guinea pig complement
• Conglutinating complement absorption test: alternative
method for the sera not fixing guinea pig complement
68.
69. OTHER COMPLEMENT DEPENDENT TESTS
• Immune adherence: When bacteria react with the specific
antibody in presence of complement and particulate materials
such as erythrocytes and platelets, bacteria are aggregated
and adhere to the cells.
• Immobilisation test e.g. Treponema pallidum
immobilisation test
• Cytolytic or cytocidal tests: also complement dependent;
e.g. measure anticholera antibodies
• Immunoflouresence test: can also use labelled
complements for detection of Ag or Ab.