Immune Disorders Flashcards
Immune system
The immune system is a collection of mechanisms that protect against disease by identifying and killing pathogens, and tumour cells, and protection against microbial toxins.
Immunology
Immunology is the science that examines the structure and function of the immune system.
Pathogens
Include: viruses, bacteria, mycobacteria, parasites, and fungi.
GENERAL CHARACTERISTICS OF IMMUNITY
Recognition: The ability to distinguish between normal self, altered (damaged) self and non-self (foreign material)
Specificity: The ability to inactivate, destroy and remove the “offending” material, without damaging normal tissues in the vicinity of the reaction, i.e. the reaction must be target-specific.
Regulation: The immune system is able to control the type, intensity and duration of the reaction and has the ability to prevent immune reaction (suppression).
Amplification: The effector (attack) phase of the immune reaction is mediated through multiple pathways which act synergistically for optimal effect. Each pathway has built-in amplification systems, too. All these systems have different triggering points and each may be triggered independently, but eventually involve the other systems.
Memory: The identity of the foreign material (antigen) which led to the first (primary) immune response is remembered so that the next episode involving the same antigen will result in an accelerated reaction (secondary immune response), which by-pass several initial steps that the primary immune response has to go through. Immunological memory is what confers long-term immunity against infections.
Defense against microbial invasion involves two types of systems
innate and acquired (adaptive) immunity
- Our innate immune system does not require prior exposure to a microbe to mount an immune response – it is always present and ready to attack.
- Acquired immunity is a more advanced system requiring exposure to an antigen in order to become active against microbes which have evaded the innate system
CHARACTERISTICS OF THE INNATE (NATURAL) IMMUNE SYSTEM
Exposure leads to immediate maximal response.
It is non-specific.
It does not require a previous exposure to an offending agent (antigen).
Found in nearly all forms of life
CHARACTERISTICS OF THE ADAPTIVE (ACQUIRED) IMMUNITY
Pathogen and antigen specific response.
Lag time between exposure and maximal response.
Cell mediated and humoral (antibody) components.
Cell mediated and humoral components (of inflammatory response).
Exposure leads to immunological memory.
Found only in jawed vertebrates.
THE INNATE IMMUNE RESPONSE
takes place when a microorganism is able to break through the normal epithelial barriers of the skin, GI and respiratory tract.
Phagocytes ingest microbes and secrete cytokines which stimulate the inflammatory response.
Cells have various receptors (pattern recognition receptor) that are able to recognize components that are preserved among broad groups of microorganisms.
COMPONENTS OF THE INNATE IMMUNITY
- Surface barriers
- Mechanical, such as skin
- Chemical, such as enzymes in saliva, vaginal secretions and tears
- Biological, such as bacterial flora in different organs - Humoral and chemical barriers
- Inflammation
- Complement system
Inflammation - innate immunity
Inflammation is one of the first responses of the immune system to infection.
It is produced as a result of release of:
- Cytokines (such as interleukins) released by infected or injured cells
- Prostaglandins
- Leukotrienes
- Chemokines
- Interferons
The cellular components of inflammation are:
- Neutrophils: phagocyte and release enzymes.
- Eosinophils and basophils: secrete chemical mediators.
- Monocytes/macrophages: attack pathogens by engulfing and then killing the microorganism by enzymes present within “lysosomes”.
- Mast cells: regulate the inflammatory response.
- Dendritic cells: phagocyte.
- Natural killer cells.
Complement system - innate immunity
It consists of more than 20 proteins and named as such due to its ability to “complement” the killing of a pathogen. They are synthesized mainly in the liver and normally circulate in the blood in an inactive form.
The complement proteins can be activated by:
- Proteases (damaged cells, bacterial endotoxins), or
- Binding of the complement to antibodies that are attached to microbes, or
- Binding complement to carbohydrates on the microbes’ surfaces.
The complement activation results in:
- Cell membrane disruption (lysis of target cell), or
- Opsonization (coat) an organism, marking it for destruction, or
- Attraction of other immune cells through the production of peptides.
- Complement activation also results in the release of various factors, e.g. anaphylatoxins and chemotactic factors which result in acute inflammation. Certain products of complement activation can also trigger the coagulation system, kinin system and fibrinolytic system.
Invasion by microbes
Invasion by microbes occurs across the main epithelial barriers. Epithelia are a physical barrier to entry.
Once across the epithelium, microbes face attack by phagocytes, including macrophages that reside within the subepithelial tissues, and neutrophils which are rapidly recruited to the site
Phagocytes recognize microbes through evolutionarily conserved receptors, especially Toll-like receptors (TLRs). These are a family of ‘pattern-recognition’ receptors that recognize products of bacteria (endotoxin, etc), viruses (double-stranded RNA), and other pathogens
The phagocytes kill microbes by ingesting them (phagocytosis) and the production of microbicidal substances. Phagocytes (and dendritic cells) also produce cytokines that enhance the killing of microbes and recruitment and activation of other cells of the immune system.
Natural killer cells
Natural killer cells recognize class I MHC molecules, which are present on all healthy cells. NK cells express inhibitory and activating receptors.
The receptor for MHC class I is an inhibitory receptor, therefore NK cells will be ‘inhibited’ from attacking normal healthy cells.
However, if a cell is damaged or abnormal (i.e. virally-infected cell, tumour cell), such that MHC I is abnormal or not expressed, NK cells will kill them. In addition, damaged or stressed cell may express molecules that bind to the activating receptors on NK cells. In the absence of normal MHC I, NK cells will become activated to kill these cells.
NK cells also function as part of the adaptive immune system by recognizing antibody coated cells, which they will also kill (antibody-mediated cytotoxicity).
NK cells also produce the cytokine interferon- in order to activate macrophages.
Plasma proteins
Some plasma proteins, particularly the complement system, recognize components of microbes (endotoxin, mannose residues) and are activated.
The complement system consists of a group of proteins that are present in plasma in inactive form. Once activated via proteolysis, they may form complexes with other complement proteins to kill microbes by direct cell lysis (membrane attack complex).
They may also act as inflammatory mediators to recruit leukocytes, or may act as opsonins (C3b), coating microbes to target them for phagocytosis
ACQUIRED (ADAPTIVE) IMMUNITY
Adaptive immunity is dependent on several cell types (lymphocytes, antigen-presenting cells, some phagocytes). Specificity is achieved through the recognition of specific antigens and expression of MHC molecules on particular cell types.
It allows for stronger immune responses and immunological memory, and requires the recognition of a specific foreign (non-self) antigen.
The system is highly malleable due to the somatic hypermutation and V(D)J recombination of antigen receptor genes. This process allows a small number of genes to generate an enormous number of antigen receptors that are uniquely expressed on each individual lymphocyte.
Components of adaptive immunity
- Lymphocytes
- T lymphocytes
- B lymphocytes
- Natural Killer (NK) cells - Other cells
- antigen-presenting cells: dendritic cells, macrophages
- phagocytes: macrophages - Human major histocompatibility complex (MHC)
The major functions of the adaptive immune system include
The recognition of specific “non-self” antigens during the process of antigen presentation.
The generation of responses that are tailored to maximally eliminate specific pathogens or pathogen-infected cells.
The development of immunologic memory, in which a signature antigen in each pathogen is “remembered” or “recognized”. These memory cells can be recruited to quickly eliminate a pathogen if a subsequent infection occurs.
T-LYMPHOCYTES
They originate from primitive stem cells (yolk sac in embryos and bone marrow after birth), and mature in the thymus gland.
They constitute 60 to 70% of peripheral blood lymphocytes.
Each cell is programmed to recognize a specific cell-bound antigen by means of an antigen-specific T-Cell Receptor (TCR). TCRs are linked to a cluster of five polypeptide chains, called CD3 molecular complex. CD3 molecules do not bind antigen but are involved in the transduction of signals into the T cell after it has bound the antigen
T lymphocytes also express a variety of other molecules including CD4 or CD8. [CD=cluster of differentiation]. CD4 (expressed on ~60% of mature CD3+cells) and CD8 (expressed on ~30% of T cells) are very important. They provide the Helper/inducer and suppressor/cytotoxic functions respectively. Antigens are presented to T cells by accessory cells (antigen-presenting cells) that carry an appropriate histocompatibility (MHC) molecule.
B-LYMPHOCYTES
Constitute 10-20% of peripheral lymphocytes. Arise from yolk sac in embryos, and bone marrow after birth. They mature in the Bone marrow.
Immature B-cells (pre-B) contain cytoplasmic heavy-chain immunoglobulins (Ig). Later, they develop surface immunoglobulins (Ig).
Mature B-cells are primarily in a resting state, awaiting activation by foreign antigen. On antigenic stimulation, they form plasma cells which secrete 5 classes of immunoglobulins (M, G, A, D, E).
Like the T lymphocytes, B-cells recognize antigen via the B-cell antigen receptor complex. The major one is IgM antigen receptor complex. Other receptors are complement receptors, IgA and IgE, CD40 and Fc receptors.
T-cells and other non-specific factors (e.g. bacterial products and certain factors) are required for maturation and differentiation of B-lymphocytes.
MACROPHAGES
They are phagocytic cells, present virtually in all body organs.
They are required to:
- Process and present antigen to immunocompetent T-cells.
- Important in certain cell-mediated immunity such as delayed hypersensitivity reaction
- Important in the effector phase of humoral immunity (phagocytose opsonized microbes).
- They secrete macrophage-derived cytokines that amplify T-cell responses.
DENDRITIC CELLS
Antigen-presenting cells:
- Interdigitating dendritic cells expresses high levels of major histocompatibility complex (MHC) antigens
- Follicular dendritic cells, bear Fc receptors for IgG
NATURAL KILLER CELLS
- 10-15% of peripheral blood cells; do not bear T-cell receptors or cell surface immunoglobulins
- They have innate ability to lyse a variety of tumour cells, viral infected cells and some normal cells without previous sensitization.
- Ability to lyse IgG-coated target cells (antibody-dependent cell-mediated cytotoxicity [ADCC]
- They have CD16 and CD56 surface molecules
- Interferon promotes their killing activity and prostaglandin E2 is highly suppressive of NK cells.
HUMAN MAJOR HISTOCOMPATIBILITY COMPLEX
The MHC is an intricate system of membrane proteins or antigens, referred to as human leukocyte antigens (HLA)
MHC genes are located on chromosome 6 and code for three major classes of molecules (designated as I, II & III).
Class III is a complement antigen and NOT a histocompatibility antigen.
Class I molecule is present on all nucleated cells and recognized by cytotoxic T-cells.
Class II is limited to:
- Antigen-presenting cells
- B-cells
- Subsets of activated T cells
SPECIFIC FUNCTIONS OF THE ACQUIRED IMMUNE SYSTEM
- ANTIGEN PRESENTATION
- CELL-MEDIATED IMMUNITY
- HUMORAL IMMUNITY
ANTIGEN PRESENTATION
SPECIFIC FUNCTION OF THE ACQUIRED IMMUNE SYSTEM
Antigen-presenting cells (APCs) reside in tissues where one of their major roles is surveillance against microbial invasion.
Microbes that gain entry through epithelial surfaces are captured by dendritic cells. Dendritic cells ingest the microbe or proteins from the microbe, then proteolytically digest them such that peptide antigens are produced.
These “extracellularly-derived” peptides are then ‘presented’ on the surface of the dendritic cell bound to MHC class II molecules.
Dendritic cells will migrate through the lymphatic system to downstream lymph nodes. Once there, the presented antigens are recognized by CD4+ helper T-cells.
Since MHC class I molecules are present on all cells, dendritic cells also express MHC class I and can present intracellular antigens (i.e. those derived from intracellular pathogens like viruses) to CD8+ cytotoxic T-cells.
CELL-MEDIATED IMMUNITY
SPECIFIC FUNCTION OF THE ACQUIRED IMMUNE SYSTEM
- CD4+ helper T-cell response
- The main function of CD4+ T-cells is to ‘help’ activate other cell types involved in immunity.
- This helper function is mediated through production of cytokines and through the expression of CD40 ligand (CD40L).
- Once activated via recognition of specific antigen presented by APCs, CD4+ T-cells secrete the cytokine interleukin-2 (IL-2), and also express a high-affinity receptor for IL-2. IL-2 induces proliferation of T-cells, allowing for expansion of an antigen-specific T-cell population.
- Some of these activated T-cells differentiate into specific types of effector T-cells that perform specific functions; these include TH1 cells that secrete IFN-, TH2 cells which secrete IL-4, IL-5, and IL-13, and TH17 cells which secrete IL-17.
- IFN-gamma activates phagocytosis and the production of antimicrobial substances in macrophages, as well as antibody production in B-cells.
- TH2 cells are mainly involved in activation of mast cells and eosinophils, rather than macrophages.
- TH17 cells are involved in activation of neutrophils.
- CD40L is expressed on the surface of CD4+ T-cells, and binds to CD40 on B-cells and macrophages to help activate them in conjunction with the secreted cytokines. - CD8+ cytotoxic T-cell response
- once activated, the CD8+ T-cells differentiate into cytotoxic lymphocytes. These cells function to destroy cells infected by microbes, often viruses or intracellular bacteria, in order to eliminate the infection.
- Recognition of infected cells occurs via MHC class I molecules: the infected cell can present peptide antigen derived from the infectious organism bound to MHC I.
- CD8+ cells specific for that antigen will bind antigen and MHC class I, then destroy the cell.
- CD8+ cytotoxic cells produce the proteins perforin and granzyme-B which are stored in cytoplasmic granules. These proteins are released into target cells (perforin allows entry of granzyme-B across plasma membrane) whereby granzyme-B triggers apoptosis via proteolytic cleavage and activation of caspases (family of proteases which activate apoptotic death).
HUMORAL IMMUNITY
SPECIFIC FUNCTION OF THE ACQUIRED IMMUNE SYSTEM
Once activated, B-cells differentiate into plasma cells or memory B-cells. Activation can occur in a T-cell-independent or –dependent manner.
- T-cell-independent activation occurs with polysaccharide or lipid antigens, which may have multiple identical epitopes that can bind to several B-cell antigen receptors.
- T-cell-dependent activation occurs with protein antigens which cannot bind to many antigen receptors, therefore full activation requires T-cell mediated cytokine stimulation coupled with CD40 ligand expression (co-activation).
Plasma cells are antibody-secreting cells.
- When a specific B-cell becomes activated, it then undergoes proliferation/clonal expansion. Some of these clonal cells differentiate into plasma cells which secrete antibodies with identical antigen-specificity to the B-cell receptor that first recognized the antigen.
- Secreted antibodies have several functions including binding to an antigen on microbes in order to neutralize them, activation of the complement system, and opsonization (coating) pathogens to target them for phagocytosis.
There are 5 classes of antibodies:
- IgG – opsonize microbes, activates complement, crosses the placenta (passive immunity)
- IgM – activates complement
- IgA – secreted in mucosal tissues (protection of mucosal epithelia)
- IgE - coats certain parasites, activates mast cells and eosinophils
- IgD – specific functions uncertain
Some cells of the immune system such as neutrophils, macrophages and natural killer cells have cell surface receptors to the Fc portion (non-variable) of antibodies, allowing them to recognize and destroy (in a nonspecific manner) opsonized cells/microbes. This is known as antibody-dependent cell-mediated cytotoxicity (ADCC).
Memory B-cells and T-cells are long-lived effector lymphocytes whose purpose is to allow fast activation upon exposure to the specific antigen they recognize.
IMMUNE DISORDERS
Disorders of the immune system may be broadly divided into:
i. Hyperfunction -Hyperfunction, usually termed HYPERSENSITIVITY, results in damage of normal tissue
ii. Hypofunction- In general, hypofunction or immunodeficiency results in two main forms of disease, as you would expect if you recall the two basic functions of the immune system:
- Defense - Disorders of defense, the most common manifestation of immune hypofunction, results in increased susceptibility to infections. The type of infection seen depends on whether cell-mediated, humoral or both forms of immunity are affected.
- Surveillance- Disorders of surveillance lead to increased frequency of malignant disease. Patients with immunodeficiency syndromes and those on immunosuppressive medications have a much higher incidence of cancer.
HYPERSENSITIVITY REACTIONS
Hypersensitivity reactions are those reactions causing tissue injury. These often represent an “excessive” immune response to an antigen. Hypersensitivity reactions may result from immune response to self-antigens (autoimmunity), reactions to microbes, or reaction to environmental antigens.
The disease states that result from hypersensitivity reactions are often chronic due to persistence of the antigens and amplification of the immune response.
There are 4 types of immune reactions which may lead to tissue damage or disease:
- Anaphylactic
- Antibody-mediated
- Immune complexes
- Cell-mediated immunity
Type I: Anaphylactic
HYPERSENSITIVITY REACTIONS
Examples: Asthma, hayfever, bee sting, peanuts
- IgE/mast cell interaction.
- Release of vasoactive amines. (e.g. histamine)
In type I, reactions result from TH2 helper T-cells, which help in the activation of IgE-producing B-cells/plasma cells. IgE molecules are attached to mast cells, which become activated and degranulate (release histamine, leukotrienes, prostaglandins and other mediators) when IgE binds antigen in a previously sensitized individual.
This are termed allergic (or atopic) reactions.
- The effects of the reaction include vascular permeability and smooth muscle contraction.
- The reaction can be localized or systemic.
- Depending on the severity, the reaction may be life-threatening (i.e. anaphylactic reaction).
TYPE II: Antibody-mediated
HYPERSENSITIVITY REACTIONS
Example: Transfusion reactions due to mismatched blood, thrombocytopenic purpura (ITP), Goodpasture syndrome.
- IgG or IgM/complement interaction
- Lysis of cells
In type II reactions, antibodies are produced which bind to antigens on surfaces of cells or tissue components. These antibodies can then activate complement, or bind to Fc receptors on phagocytes. Thus, circulating cells which are opsonized by the antibody may then be targeted for destruction by phagocytes (e.g. ITP), while other cells and tissues targeted by the antibodies are damaged secondary to complement activation and subsequent inflammation.
TYPE III: Immune complexes
HYPERSENSITIVITY REACTIONS
Example: Systemic lupus erythematosus, post-streptococcal glomerulonephritis
- Antigen-antibody complexes in the circulation are trapped in various organs (e.g. kidney) where they produce injury by complement activation and neutrophil activation
In type III reactions, antibodies are directed against circulating antigens. These antigens may be endogenous (e.g. nucleoproteins) or exogenous (e.g. proteins from microbes). The antibodies and antigens bind together to form circulating immune complexes.
Immune complexes form in the course of normal immune responses; it is only when formed in large amounts that they cause problems. These are eventually deposited in tissues where they activate complement and neutrophil-mediated inflammation.
The complexes may be deposited in blood vessels, including blood vessels of specific organs, or several tissues/organs (systemic). The tissue damage is manifested by necrotizing vasculitis (acute inflammation within the blood vessel wall with necrosis), associated ischemic necrosis and acute inflammation in the affected surrounding tissue.
TYPE IV: (Cell-mediated immunity) Two types
HYPERSENSITIVITY REACTIONS
- delayed-type hypersensitivity mediated by CD4+ T-cells
- Examples: contact dermatitis due to poison ivy, tuberculin reaction, granulomatous inflammation
- In delayed-type hypersensitivity, CD4+ T-cells differentiate into different classes of helper T-cells upon exposure to antigen via antigen-presenting cells.
- Depending on the particular cytokine(s) secreted by the APC, the T-cell differentiates into either TH1 or TH17 cells.
- Upon subsequent exposure, the differentiated Tcells migrate to the site of the antigen and are activated in conjunction with APCs.
- The TH1 cells secrete IFN- , a cytokine which activates macrophages, promoting phagocytosis and production of microbicidal substances.
- TH17 secrete IL-17, a cytokine which is chemotactic for neutrophils, recruiting them to the site of exposure and inciting acute inflammation.
- In cases of delayed-type hypersensitivity, tissue damage results.
- Formation of granulomas (def: aggregate of epithelioid macrophages surrounded by a rim of lymphocytes) occurs in some types of delayed-type hypersensitivity where there is persistence of an organism or other antigen (e.g. tuberculosis).
- The initial CD4+ T-cell infiltrate is replaced by activated macrophages which fuse to form multinucleated giant cells. - T-cell-mediated cytotoxicity, mediated by CD8+ T-cells
- Examples: viral hepatitis, type I diabetes, solid-organ transplant rejection
- In T-cell mediated cytotoxicity, CD8+ cells destroy cells expressing a particular antigen (eg. self antigen expressed on islet cells of the pancreas in type I diabetes).
Overall: Mechanisms of hypersensitivity reactions
See table for summary
AUTOIMMUNE DISEASE
Autoimmune diseases occur due to a breakdown of the normal processes which maintain a state of immunological tolerance to self-antigens.
The current concepts of immunological tolerance involve two main factors:
- Discrimination of self and non-self antigens by antigen reaction T cells (recognition).
- Suppression of immune responses to self antigens by suppressor T cells.
It is thought that autoimmunity results from two main factors:
- Genetic susceptibility to autoimmunity runs in families
- many patients have more than one autoimmune disease
- particular HLA alleles are linked to autoimmune diseases
- genetic polymorphisms are linked to autoimmune diseases - Environmental factors
- microbes including viruses and bacteria may trigger autoimmune diseases
- UV radiation
- ?smoking
- tissue damage
- ?hormones
The clinical picture in the different autoimmune diseases depends on:
a) the target (antigen).
b) type of immune reaction (cell-mediated, humoral or both).
c) changes secondary to the destruction of the target organ or type of immune reaction
Autoimmune disease examples
- Systemic lupus erythematosus:
a) Target: DNA
b) Immune reaction: Type III - circulating DNA-antiDNA complexes
c) Dermatitis, nephritis, arthritis: Due to trapping of complexes in skin, kidneys and joint synovium.
- Hashimoto’s thyroiditis:
a) Target: thyroid follicular cells
b) Immune reaction: Type II - cytotoxic antibody - complement activation Type IV - cell-mediated
c) Hypothyroidism due to the destruction of thyroid cells.
Immunodeficiency diseases - Clinical features
Primary (congenital); Secondary (acquired)
Clinical Features Associated With Immunodeficiency
1. Chronic infection.
2. Recurrent infection (greater frequency than expected).
3. Unusual infecting agents (low pathogenic potential).
4. Poor resolution or poor response to antibiotic treatment.
Primary Immunodeficiency Diseases
Certain generalizations may be made regarding immunodeficiency syndromes:
- Cell-mediated immune deficiencies (T-cell dysfunction) may present very early (such as during the neonatal period) (e.g. DiGeorge syndrome - congenital absence of thymus). It usually affects the humoral system as well because of a lack of helper/suppressor effect on B cells. Thus, pure T cell dysfunction is unlikely
- Pure B cell dysfunction (with normal T cell function) is possible (e.g. Bruton’s syndrome).
- Pure B cell dysfunction is not detected until the infant is 5-6 months old, because of protection by maternal IgG antibodies.
- Both T and B cell deficiency can occur in the same patient (e.g. severe combined immunodeficiency disease).
- Specific primary (congenital) immunodeficiency disorders
Autoimmune disease - Disorders affecting lymphocyte function
- X-linked agammaglobulinemia
- Common variable immunodeficiency
- Isolated IgA deficiency
- Hyper-IgM syndrome
- DiGeorge syndrome
- Severe combined immunodeficiency
Recurrent infections may also occur in the presence of intact T and B cell function. These are due to defects in the amplification systems, e.g. deficiency of specific complement components, disorders of the mononuclear phagocytic system and of the granulocyte series.
Chronic granulomatous disease results from phagocytic dysfunction (absence of lysosomal enzymes in monocytes and granulocytes).
Autoimmune disease - Disorders affecting innate immunity
Deficiency of complement proteins
Chronic granulomatous disease (defect in NADPH oxidase)
Rare mutations in Toll-like receptors
Secondary Immunodeficiency Diseases
These may occur due to:
- Infections:
- Rubella—–>Temporary
- Measles —–> Immuno
- Mycoplasma —–>deficiency
- Human Immunodeficiency Virus (HIV) —-> Acquired Immunodeficiency Syndrome (AIDS). - Immunosuppressive therapy: i.Cytotoxic drugs, cortisone (e.g. chemotherapy for cancer) ii.Irradiation iii.Anti-lymphocyte serum globulin (ALG)
- Malignancy (especially lymphoma)
- Chronic illness
- Malnutrition
- Aging
