Proteins on Cell Membranes and Immune Response

Complement Activation

• The third pathway of complement activation is initiated by mannan-binding lectin (MBL), a surface receptor that binds to carbohydrates on microbial surfaces.
• MBL activates C4 and C2, which then split into "a" and "b" fragments, generating enzyme activity (C1 esterase).
• The complex C4b2b is the classical pathway C3 convertase, which cleaves C3 into active fragments.

Complement Components

• C3b is an opsonin that marks pathogens for phagocytosis.
• C5a and the activated complex C567 are potent mediators of inflammation.
• C5b initiates the formation of the membrane attack complex (MAC), which forms a hollow, thin-walled cylinder through which salts and water flow, leading to the uptake of water by a cell and its destruction.

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

• ADCC is an additional mechanism by which bacteria and viruses can be eliminated.
• ADCC is mediated by engagement of the receptor NKR-P1 with its carbohydrate ligand on the target cell.

Immune Effector Molecules

• Humoral immunity: specific antibodies for opsonization and phagocytosis or lysis with complement.
• Cellular immunity: perforin in NK cells and cytolytic (CD8) T cells creates pores in target cell membranes, allowing entry of granzymes to cause apoptosis.

T-Cell Receptor (TCR)

• The TCR is composed of alpha (α) and beta (β) chains, which make up the T idiotype, i.e., the antigen/peptide binding region.
• The TCR is closely associated with the CD3 protein on the cell surface, which is essential for activation.
• Recognition of processed antigen alone is not enough to activate T cells; accessory molecules like CD4 and CD8 are required for increased binding and signaling.

Introduction to Immune System

• The term "allergy" is often misused to describe any intolerance of environmental factors, regardless of evidence of immunological reactivity to an identified antigen.
• The normal immune system is the basis for understanding how it can go wrong and cause disease.

Key Molecules in Immune Response

• Antibodies recognize specific antigens and are surface receptors of B cells (BCRs).
• Activated B cells secrete antibodies into blood and body fluids to prevent antigen damage.
• T cells have structurally similar receptors for recognizing antigens, known as T-cell receptors (TCRs).
• Major histocompatibility complex (MHC) molecules provide self-recognition and play a fundamental role in T lymphocyte effector functions.

Innate and Adaptive Immunity

• Innate immunity recognizes general patterns of 'foreignness' on non-mammalian cells through detection molecules.
• Adaptive immunity recognizes a wide range of particular molecules or fragments of molecules through specific detection molecules.
• Innate immunity includes recognition of structures shared by microbes, activation of dendritic cells, and phagocytic cells recognizing particular patterns associated with potentially damaging materials.
• Adaptive immunity includes recognition of antigens, which are molecules that interact with T- and B-cell recognition receptors and antibodies.

Antigens and Epitopes

• Antigens are substances recognized by immune components.
• An antigenic molecule can have several antigenic determinants (epitopes).
• Each epitope can bind with an individual antibody, and a single antigenic molecule can provoke many antibody molecules with different binding sites.

Adjuvants

• Adjuvants are substances that improve an immune response to a separate, often rather weak, antigen.
• Adjuvants are used in humans, particularly in vaccines against infective agents and tumours, and are discussed in section 7.3.2.

Introduction to Immune System

• Allergy is a misunderstood term, often used loosely to describe any intolerance of environmental factors without objective evidence of immunological reactivity to an identified antigen.

Key Molecules in Immune Response

• Antibodies are surface receptors of B cells (BCRs) that recognize specific antigens and are also secreted into blood and body fluids in large quantities to prevent antigen damage.
• T cells have structurally similar receptors for recognizing antigens, known as T-cell receptors (TCRs).
• Major histocompatibility complex (MHC) molecules provide a means of self-recognition and play a fundamental role in T lymphocyte effector functions.

Innate and Adaptive Immunity

• Innate immunity recognizes general patterns of ‘foreignness’ on non-mammalian cells through detection molecules on innate cells.
• Adaptive immunity recognizes a wide range of very particular molecules or fragments of molecules through detection molecules on adaptive cells.
• Antigens are substances that are recognized by immune components.

Antigen Characteristics

• An antigenic molecule may have several antigenic determinants (epitopes).
• Each epitope can bind with an individual antibody.
• A single antigenic molecule can therefore provoke many antibody molecules with different binding sites.

Adjuvants

• Substances that improve an immune response to a separate, often weak, antigen are known as adjuvants.
• Adjuvants are used in humans, particularly in vaccines against infective agents and tumors.

Developmental Pathway for Natural Killer Cells

• The developmental pathway for natural killer (NK) cells is separate from other immune cells because NK cells may develop in both the thymus and the bone marrow.

Effector Mechanisms and Soluble Mediators

• Effector mechanisms often depend on messages from initiating or regulating cells.
• Soluble mediators, which carry messages between cells, are known as interleukins, cytokines, and chemokines.

Factors Influencing the Immune Response to an Antigen

• The immune response to an antigen is influenced by factors such as:
  • Nature of the molecule (protein content, size, solubility)
  • Dose (low, moderate, or high)
  • Route of entry (ID, IM, SC, IV, oral, inhalation)

Molecules Recognized by the Immune System

• Foreign substances are recognized by both the innate and adaptive systems, but in different ways, using different receptors.
• The innate system is activated by 'danger signals' due to pattern recognition receptors (PRRs) on dendritic cells recognizing conserved microbial structures directly.
• Toll-like receptors (TLRs) make up a large family of non-antigen-specific receptors for a variety of individual bacterial, viral, and fungal components.

Natural Killer Cells

• NK cells look like large granular lymphocytes and are found in blood, liver, and secondary lymphoid organs, particularly the spleen and mucosal-associated lymphoid tissue (MALT).
• NK cells can kill target cells, even in the absence of antibody or antigenic stimulation.
• They play a role in early immune response to viral infection, producing type-I interferons and IL-12, and later, T cell-mediated killing by antigen-specific cells (cytotoxic T cells, CTL).

Activation of Toll-like Receptors on Dendritic Cells

• Engagement of Toll-like receptors on dendritic cells leads to the activation of signaling pathways, including TRAF, TNF receptor-associated factor, and IRAK, interleukin-1 receptor-associated kinase.
• This leads to the induction of pro-inflammatory cytokines and the activation of adaptive immunity.

Developmental Pathway of NK Cells

• The developmental pathway for natural killer (NK) cells is thought to occur in both the thymus and the bone marrow.

Effector Mechanisms and Soluble Mediators

• Effector mechanisms rely on messages from initiating or regulating cells.
• Soluble mediators, such as interleukins, cytokines, and chemokines, carry messages between cells.

Factors Influencing Immune Response

• Immunogenicity of an antigen is influenced by factors such as:
  • Nature of the molecule (protein content, size, solubility)
  • Dose of the antigen (low, moderate, or high doses affect antibody production)
  • Route of entry (ID, IM, SC, IV, oral, or inhalation routes affect the immune response)

Recognition of Foreign Substances

• Both innate and adaptive systems recognize foreign substances, but in different ways.
• Innate system recognizes foreign substances through:
  • Pattern recognition receptors (PRRs) on dendritic cells.
  • Toll-like receptors (TLRs) recognizing conserved microbial structures.
  • Pathogen-associated molecular patterns (PAMPs).

Toll-like Receptors

• Toll-like receptors are a family of non-antigen-specific receptors.
• They recognize individual bacterial, viral, and fungal components.
• Examples include recognition of DNA, lipoproteins, and lipopolysaccharides.

C5a and C3a

• C5a is an anaphylotoxin that causes histamine release from mast cells.
• C5a also has chemotactic activity, attracting neutrophils to the site of complement activation.

Natural Killer Cells

• NK cells are large granular lymphocytes found in blood, liver, and secondary lymphoid organs.
• They can kill target cells without antibody or antigenic stimulation.
• They produce type-I interferons and IL-12 in response to viral infection.

Role of Cells in Early Immune Response

• Early immune response involves innate immune cells producing type-I interferons and IL-12.
• Late immune response involves T cell-mediated killing by antigen-specific cells (CTL).

Immune Response

• The developmental pathway for natural killer (NK) cells is separate from other immune cells, as they may develop in both the thymus and the bone marrow.

Factors Influencing Immune Response

• The immune response to an antigen is influenced by several factors, including:
  • Nature of the molecule (protein content, size, and solubility)
  • Dose of the antigen (low, moderate, or high)
  • Route of entry of the antigen (ID, IM, SC, IV, oral, or inhalation)

Molecules Recognized by Immune System

• Foreign substances are recognized by both the innate and adaptive immune systems, but in different ways, using different receptors.
• The innate system is activated by 'danger signals' through pattern recognition receptors (PRRs) on dendritic cells, recognizing conserved microbial structures directly, such as:
  • Toll-like receptors (TLRs), a family of non-antigen-specific receptors for various individual bacterial, viral, and fungal components.
  • Pathogen-associated molecular patterns (PAMPs), often repeated polysaccharide molecules.

Natural Killer Cells

• NK cells look like large granular lymphocytes and are found in blood, liver, and secondary lymphoid organs, particularly the spleen and mucosal-associated lymphoid tissue (MALT).
• NK cells can kill target cells, even in the absence of antibody or antigenic stimulation.
• Early immune response to viral infection involves production of type-I interferons and IL-12 by innate immune cells, followed by T cell-mediated killing by antigen-specific cytotoxic T cells (CTL).

Complement System

• C5a, along with C3a, are anaphylotoxins that cause histamine release from mast cells, resulting in increased vascular permeability.
• C5a also attracts neutrophils to the site of complement activation and has chemotactic activity.
• The C3b and C4b2b3b complex generates an enzyme, C5 convertase, which initiates the final lytic pathway (the 'attack' sequence).

Immune Response

• The developmental pathway for natural killer (NK) cells is separate from other immune cells, as they may develop in both the thymus and the bone marrow.

Factors Influencing Immune Response

• The immune response to an antigen is influenced by several factors, including:
  • Nature of the molecule (protein content, size, and solubility)
  • Dose of the antigen (low, moderate, or high)
  • Route of entry of the antigen (ID, IM, SC, IV, oral, or inhalation)

Molecules Recognized by Immune System

• Foreign substances are recognized by both the innate and adaptive immune systems, but in different ways, using different receptors.
• The innate system is activated by 'danger signals' through pattern recognition receptors (PRRs) on dendritic cells, recognizing conserved microbial structures directly, such as:
  • Toll-like receptors (TLRs), a family of non-antigen-specific receptors for various individual bacterial, viral, and fungal components.
  • Pathogen-associated molecular patterns (PAMPs), often repeated polysaccharide molecules.

Natural Killer Cells

• NK cells look like large granular lymphocytes and are found in blood, liver, and secondary lymphoid organs, particularly the spleen and mucosal-associated lymphoid tissue (MALT).
• NK cells can kill target cells, even in the absence of antibody or antigenic stimulation.
• Early immune response to viral infection involves production of type-I interferons and IL-12 by innate immune cells, followed by T cell-mediated killing by antigen-specific cytotoxic T cells (CTL).

Complement System

• C5a, along with C3a, are anaphylotoxins that cause histamine release from mast cells, resulting in increased vascular permeability.
• C5a also attracts neutrophils to the site of complement activation and has chemotactic activity.
• The C3b and C4b2b3b complex generates an enzyme, C5 convertase, which initiates the final lytic pathway (the 'attack' sequence).