Learning Outcome 3: The Immune System

Part 1: The Immune System

Definition
The immune system is a complex collection of cells, tissues, and soluble mediators positioned throughout the body, whose
primary purpose is to protect us against infection.
The Immune System - Learning Objectives
After reading this chapter, you should be able to:

Introduction
The immune system has evolved to provide a coordinated response to protect the host from infection, both preventing invasion
and eradicating pathogens as quickly as possible.
A key feature of the immune system is its ability to recognize a pathogen and mount an exactly appropriate response.
Inappropriate responses can result in disease, including conditions such as autoimmunity or hypersensitivity.
Three Layers of Immune Protection

The first line of defense: physicochemical barriers (e.g., skin, mucosal epithelia) and their secreted products.
The second line of defense: innate immunity, a nonspecific response to a wide range of pathogens.
The third level of defense: the adaptive immune response, a highly specific defense activated when innate immunity is
insufficient.
Signs of Inflammation

Innate immunity is the body's immediate, nonspecific response to infection and is often associated with inflammation.
Monocytes Transform into Macrophages

Monocytes transform into macrophages, which play a crucial role in phagocytosis, antigen presentation, and the removal of
damaged host cells.
Receptors for Recognizing Attacking Microbes

Neutrophils and macrophages use pattern recognition receptors (PRRs) to identify structures shared by various microbes, known
as pathogen-associated molecular patterns (PAMPs).
Pattern Recognition Receptors (PRRs)

PRRs are classified into categories based on location and function.

Toll-like receptors (TLRs) are a well-characterized PRR family, with 10 expressed TLR genes in humans.
Inflammatory Mediators

Innate immune cells like neutrophils and macrophages produce inflammatory mediators, which can directly kill pathogens and
recruit and activate other immune cells.
Cytokines in Inflammatory and Immune Responses

Cytokines are small peptides or glycoproteins produced by various cell types, including macrophages and T cells, and play a
crucial role in inflammation and immune responses.
Classification of Cytokines by Principal Effect

Cytokines are categorized into families based on their principal effects, including colony-stimulating factors, interferons,
interleukins, tumor necrosis factor (TNF), and chemokines.
Dendritic Cells Link Innate and Adaptive Immune Responses

Antigen-presenting cells (APCs), especially dendritic cells (DCs), display microbial antigens to initiate the adaptive immune
response.
DCs have the unique ability to migrate from infected tissues to lymph nodes, where they activate naïve T cells, initiating the
adaptive immune response.
Function of Interdigitating Dendritic Cells

Adaptive immune responses become essential when innate defenses fail. These responses are slower but highly specific and
effective.
The major cell types in adaptive immunity are T cells and B cells, which recognize antigens and trigger an adaptive response.
Distinct Cell-Surface Markers for T and B Lymphocytes

T and B lymphocytes are effector cells in adaptive immunity, with surface markers identified using the cluster of differentiation
(CD) system.
Similarity in Structure of T and B Cell Antigen Receptors

T and B cells both have antigen receptors but recognize different forms of antigens, initiating specific adaptive immune
responses.
An Overview of Lymphocyte Responses

Part 2: The Immune System

Adaptive immune responses become crucial when innate defenses fail.

The adaptive response is slower than the innate response but highly specific and effective.
The two primary cell types in the adaptive immune system are T cells and B cells, collectively known as lymphocytes, and they
play a pivotal role in immune defense.
The adaptive response starts when lymphocytes recognize components of infectious agents known as antigens.
Antigens binding to receptors on lymphocytes trigger an adaptive response.
Distinct Cell-Surface Markers for T and B Lymphocytes

Effector cells primarily involved in the adaptive immune response are T and B lymphocytes.
Lymphocytes are present in the peripheral blood at 1.3–4.0 × 109/L, with T cells comprising 50%–70% and B cells 10%–20% of
the total.
Identification of T- and B-cell lineages can be done through flow cytometry to determine their receptor expression or functional
studies.
Surface markers on lymphocytes and other immune cells are classified using the cluster of differentiation (CD) system. For
example, T cells are CD4 or CD8 positive, while B cells are CD19 positive.
T and B cells have distinct antigen-recognition receptors.
Similarity in Structure of T and B-Cell Antigen Receptors

While T and B cells have different antigen receptors, there is great diversity in the precise shape of the antigen-recognition
receptor on each cell, contributing to the exquisite specificity of the adaptive immune response.
Each antigen is recognized by only one or a few T and B cells.
Upon encountering their specific antigen and receiving additional costimulatory signals, lymphocytes become activated,
proliferate, and differentiate.
T-Cell Antigen Receptor (TCR)

The T-cell antigen receptor, TCR, is complexed with CD3 and plays a crucial role in signal transduction.
MHC Proteins and Antigen Presentation

For an immune response to initiate, antigen must be presented formally to the immune system.
Antigen-presenting cells (APCs) express processed antigenic peptides within grooves of major histocompatibility complex (MHC)
molecules on their cell surface.
Genetic organization of MHC genes is grouped into three regions: class I, class II, and class III.
Class I and II MHC molecules are directly involved in immune recognition and cellular interactions, while class III molecules are
involved in the inflammatory response.
B-Cell Antigen Receptor (BCR)

The B-cell antigen receptor (BCR) is a membrane form of immunoglobulin molecules found circulating in serum.
Immunoglobulins are Y-shaped molecules with heavy and light chains, forming antigen-binding sites.
The constant amino acid sequence domains of chains constitute the stem of the Y-shaped molecule, and the Fc portion has
various functions, including signaling for BCR.
Activation of the Adaptive Immune System

Cells and molecules of adaptive immunity, including CD4+ helper T cells, CD8+ cytotoxic T cells, and antibodies produced by
activated B cells, work together to eradicate pathogens.
The adaptive immune response involves both cellular and humoral elements, with T cells mediating cellular immunity and B
cells responsible for humoral immunity.
For example, macrophages increase phagocytosis in response to cytokines released by T cells, and opsonization, the coating of
microbes with antibodies, enhances phagocytosis by neutrophils and macrophages.
Natural Killer Cells (NK Cells)

Natural Killer cells destroy infected and malignant cells through recognition via Fc receptors and killer activating receptors.
Killer inhibitory receptors recognize MHC class I molecules, and loss of MHC class I on cells makes them targets for NK cell
attack.
NK cells release cytotoxic granules containing perforin and granzymes to kill target cells.
Summary of the Adaptive Immune System

Effector functions of antibodies and cellular responses contribute to the destruction of invading organisms.
Recruitment of leukocytes is regulated by chemokines and adhesion molecules.
Effector functions of innate immune system cells include phagocytosis, production of reactive oxygen intermediates, and
hydrolytic enzyme activity.
Host tissues may also be damaged in the process.
Chronic inflammation may occur when pathogens are resistant to destruction or inadequately regulated.

Part 3: Hypersensitivity
Hypersensitivity responses are immune reactions where the immune system acts defensively but causes damage.
Influenced by both autoimmunity and allergies.
Autoimmune infections involve immune responses against the body's own tissues, while allergies involve reactions to common
environmental substances.
Hypersensitivity responses are classified into four groups (Type I, Type II, Type III, and Type IV) based on mechanisms.
Gell and Coombs proposed this classification in 1963.
Classification of Hypersensitivity Responses

Gell and Coombs classified hypersensitivity responses into four types based on mechanisms.
Type I: Immediate allergic reactions (e.g., anaphylaxis).
Type II: Antibody-mediated cytotoxic response to specific tissues.
Type III: Mediated by antibody-antigen complexes causing tissue damage.
Type IV: Cell-mediated responses involving sensitized T helper cells.
A fifth type of hypersensitivity describes immune responses affecting the endocrine system in some autoimmune diseases.
Type I Hypersensitivity

Type I hypersensitivity is an immediate allergic response mediated by IgE antibodies.

It results in anaphylaxis in response to substances such as insect venoms, drugs, and food.
Allergic reactions occur due to the induction of IgE antibodies to allergens.
Antigen cross-linking with membrane-bound IgE on basophils or mast cells triggers the release of histamine, causing tissue
damage.
Treatment for Type I Hypersensitivity Disorders

Avoid allergens.
Antihistamines compete with histamine for receptors, effectively blocking histamine receptor sites.
Epinephrine is the best immediate treatment for anaphylactic shock.
Cortisone blocks histamine synthesis.
IgE Effects on Mast Cell Function and Immune Responses

Stimulation of mast cells with IgE enhances sensitivity to antigen.

IgE triggers the secretion of various mediators that alter immune responses.
Type II Hypersensitivity

Type II hypersensitivity involves toxic properties of antibodies attached to antigens on cell surfaces.
Antibodies can activate complement-dependent lysis leading to tissue damage.
Examples include Rh-incompatibility in newborns, blood transfusion reactions, Goodpasture's syndrome, and autoimmune
reactions.
Type III hypersensitivity is facilitated by antigen-antibody complex formation.
IgG and IgM bind to antigens, deposit immune complexes, and stimulate complement.
This results in PMN chemotaxis and the release of tissue-damaging enzymes.
Serum sickness is a common example of Type III hypersensitivity.
Type IV Hypersensitivity (Delayed Hypersensitivity)

Type IV hypersensitivity is cell-mediated and takes 12-24 hours to develop, lasting 2-3 days.
It involves T-lymphocytes and effector T-cells.
Antigens on lymphocyte surfaces can induce cytokine release, damaging cells.
Conditions like tuberculosis exhibit delayed-type hypersensitivity.

Part 4: Concept of Self-Tolerance

Concept of Self-Tolerance
Immunologic specificity of T and B cell antigen receptors results from random gene shuffling in DNA coding for the antigen-
binding site.
This process can generate various T-cell receptors, including those that can bind to autoantigens, known as self-reactive T cells.
Autoimmunity

Autoimmunity involves the presence of antibodies and T cells directed against a person's own normal components, known as
autoantigens.
Autoantigens or self-antigens are typically proteins or protein-nucleic acid complexes.
Autoantibodies and autoreactive T cells target autoantigens.
Tolerance is the process that eliminates or neutralizes autoreactive cells.
Autoimmunity results from a breakdown in tolerance, causing the immune system to inappropriately destroy healthy cells,
limiting tissue function or tissue restoration strategies.
Immunosuppression

Current approaches for addressing the destruction of healthy cells involve immunosuppression.
Immunosuppression nonspecifically inhibits immune responses, targeting T or B cell subsets, antigen presentation, cytokine
production, or lymphocyte trafficking.
It is commonly used to treat autoimmune diseases or transplant rejection.
Central T-Cell Tolerance

T-cell tolerance primarily occurs in the thymus by deleting self-reactive T cells.

Immature T cells migrate from the bone marrow to the thymus and encounter peptides from endogenous proteins bound to
major histocompatibility complex (MHC) molecules.
T cells with low or high affinity for self peptides bound to MHC molecules undergo apoptosis.
T cells with intermediate affinity mature and migrate to the periphery, where they can become activated.
Peripheral Mechanisms of the Induction of Tolerance

T cells separated from their specific antigen, for example, by the blood-brain barrier, cannot be activated, a concept known as
immunologic ignorance.
T cells expressing the Fas (CD95) molecule can undergo apoptosis when they receive signals from cells expressing Fas ligand,
referred to as deletion.
Dendritic Cells

Dendritic cells play a crucial role in regulating immune responses and tolerance.
Monocyte-derived dendritic cells can differentiate into activated or tolerogenic dendritic cells.
This differentiation is relevant in cancer immunotherapy and autoimmune disorders.
Summary

Autoimmunity
Autoimmunity involves three major phases.
Factors responsible for initiating autoimmunity include genetic susceptibility, environmental stimuli, and defective regulation.
 Part5: Transplantation Immunology

Transplant immunology studies the immune response when an organ or tissue is transplanted from one individual to another.
A major challenge in transplantation is the recipient's immune system viewing the graft as foreign and attacking it.
History of Transplant Immunology

Significant milestones in the history of successful transplants:

1905: First successful cornea transplant by Eduard Zirm
1954: First successful kidney transplant by Joseph Murray
1966: First successful pancreas transplant by Richard Lillehei and William Kelly
1967: First successful liver transplant by Thomas Starzl
1967: First successful heart transplant by Christiaan Barnard
1981: First successful heart/lung transplant by Bruce Reitz
1983: First successful lung lobe transplant by Joel Cooper
1986: First successful double-lung transplant by Joel Cooper
1987: First successful whole lung transplant by Joel Cooper
And more recent achievements in transplant history.
Basic Concepts and Definitions

Rejection results from the recipient's immune response to genetically different elements in the transplanted organ.
These elements are called transplantation antigens or alloantigens.
The transplanted organ is referred to as an allogeneic graft or allograft.
The immune response against it is the alloimmune response.
Alloreactive refers to reacting in response to a transplanted allograft.
Classification of Grafts

Autologous grafts (Autografts): Transplanted within the same individual.

Syngeneic grafts (Isografts): Transplanted between genetically identical individuals of the same species.
Allogeneic grafts (Allografts): Transplanted between genetically different individuals of the same species.
Xenogeneic grafts (Xenografts): Transplanted between individuals of different species.
Tissue Transplantation

Regardless of origin, tissues are considered immunogenic when transplanted.

Surgical transplantation bypasses physical immune barriers, relying on innate and adaptive immune responses for protection.
Innate Immune Response

The innate immune response is activated after transplantation but does not necessarily cause graft rejection.
Antigens from the transplant and cytokines stimulate the activation of the adaptive immune response.
Direct and Indirect Activation of Adaptive Immune Response

Direct activation involves donor dendritic cells migrating from the allograft to secondary lymphoid organs.
Indirect activation is mediated by recipient dendritic cells processing alloantigens expressed on donor cells.
Central and Peripheral Tolerance

Central tolerance occurs in the thymus, where self-antigens are expressed on medullary thymic epithelial cells.
Peripheral tolerance mechanisms control self-reactive T cells in the periphery.
Both central and peripheral tolerance are crucial for preventing graft rejection.
Strategies for Achieving Tolerance

The goal of transplantation is to induce immunologic tolerance to the transplant without immunosuppression.
Strategies include deletion (removing donor-reactive immune cells), immunologic ignorance, anergy (nonresponsiveness), and
active inhibition by Tregs (regulatory T cells).
Current Approaches for Diagnosis of Rejection

Various diagnostic methods are employed to detect rejection after solid organ transplantation.