Cell-Mediated Immune Response is the body’s ability to stay safe by affording protection against harmful agents and involves lines of defense against most microbes as well as a specialized and highly specific response to a particular offender. This immune response classifies as either innate which is non-specific and adaptive acquired which is highly specific. The innate response, often our first line of defense against anything foreign, defends the body against a pathogen in a similar fashion at all times. These natural mechanisms include the skin barrier, saliva, tears, various cytokines, complement proteins, lysozyme, bacterial flora, and numerous cells including neutrophils, basophils, eosinophils, monocytes, macrophages, reticuloendothelial system, natural killer cells (NK cells), epithelial cells, endothelial cells, red blood cells, and platelets.
The adaptive acquired immune response will utilize the ability of specific lymphocytes and their products (immunoglobulins, and cytokines) to generate a response against the invading microbes and its typical features are[rx][rx][rx]:
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Specificity: as the triggering mechanism is a particular pathogen, immunogen or antigen.
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Heterogeneity: signifies the production of millions of different effectors of the immune response (antibodies) against millions of intruders.
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Memory: The immune system has the ability not only to recognize the pathogen on its second contact but to generate a faster and stronger response.
The inflammatory immune response is an example of innate immunity as it blocks the entry of invading pathogens through the skin, respiratory or gastrointestinal tract. If pathogens can breach the epithelial surfaces, they encounter macrophages in the subepithelial tissues that will not only attempt to engulf them but also produce cytokines to amplify the inflammatory response.
Active immunity – results from the immune system’s response to an antigen and therefore is acquired. Immunity resulting from the transfer of immune cells or antibodies from an immunized individual is passive immunity.
The immune system has evolved for the maintenance of homeostasis, as it can discriminate between foreign antigens and self; however, when this specificity is affected an autoimmune reaction or disease develops.
Clonal Selection and T-Cell Differentiation
Antigens are selected to form clones of themselves, both memory and effector.
Key Points
All T cells originate from hematopoietic stem cells in the bone marrow and generate a large population of immature thymocytes. The thymocytes progress from double-negative cells to become double-positive thymocytes (CD4+CD8+), and finally mature to single-positive (CD4+CD8- or CD4-CD8+).
Clonal selection is used during negative selection to destroy lymphocytes that may be able to bind with self-antigens.
Clonal selection is the theory that specific antigen receptors exist on lymphocytes before they are presented with an antigen due to random mutations during initial maturation and proliferation. After antigen presentation, selected lymphocytes undergo clonal expansion because they have the needed antigen receptor.
Clonal selection may explain why memory cells can initiate secondary immune responses more quickly than the primary immune response, due to increased binding affinity from clonal expansion.
During T cell differentiation, the naive T cell becomes a blast cell that proliferates by clonal expansion and differentiates into memory and effector T cells.
Many subsets of helper T cells are created during T cell differentiation and perform vastly different functions for the immune system.
Key Terms
- Clonal selection: The idea that lymphocytes have antigen-specific binding receptors before they encounter an antigen, and are selected to proliferate because they have the specific antigen receptor needed during an adaptive immune response.
Clonal selection is a theory that attempts to explain why lymphocytes are able to respond to so many different types of antigens. T and B cells are able to respond to nearly all of the world’s vast variety of antigens upon presentation. Clonal selection assumes that lymphocytes are selected during antigen presentation because they already have receptors for that antigen.
Clonal Selection
In clonal selection, an antigen is presented to many circulating naive B and (via MHC) T cells, and the lymphocytes that match the antigen are selected to form both memory and effector clones of themselves. This mass production is termed “clonal expansion,” in which daughter cells proliferate into several generations of clones of the original parent cells. The theoretical basis of clonal selection is the assumption that lymphocytes bearing an antigen receptor for an antigen exist long before antigen presentation occurs, explained by the idea of random mutations (VDJ recombination) that occur during lymphocyte maturation. During antigen presentation, pre-existing lymphocytes that bear that antigen receptor are merely selected because they can bind with that antigen. It is also assumed that most lymphocytes never encounter the antigen for which they bear a receptor.
Clonal selection may also be used during negative selection during T cell maturation. Here, the body’s own epitopes are presented to the infant lymphocytes; those that react are recognized as auto-reactive and destroyed before they (and their future cloned daughter cells) can leave and wreak havoc in the body. This assumes that random mutations resulted in lymphocytes that were autoreactive instead of reactive to non-self antigens.
Following an adaptive immune response, memory cells are able to respond to a new infection of the same pathogen much more quickly than the original effector T cells during the formation of the adaptive immune response. Clonal selection is thought to cause mutations of antigen-binding affinity in memory cells during clonal expansion so that memory cells have greatly increased antigen-binding affinity than the effector cells during the first response. The increased binding affinity may be why memory cells can eliminate a pathogen more rapidly than the original generation of effector cells. This idea is still only a theory but explains many of the nuances of the adaptive immune system.
Clonal selection of lymphocytes: A hematopoietic stem cell undergoes differentiation and genetic rearrangement to produce lymphocytes in the immune system. Clonal selection of lymphocytes: 1) A hematopoietic stem cell undergoes differentiation and genetic rearrangement to produce 2) immature lymphocytes with many different antigen receptors. Those that bind to 3) antigens from the body’s own tissues are destroyed, while the rest mature into 4) inactive lymphocytes. Most of these will never encounter a matching 5) foreign antigen, but those that do are activated and produce 6) many clones of themselves.
T Cell Differentiation
Following T cell maturation, naive T cells circulate through the circulatory and lymphatic systems of the body until presented with an antigen for which they bear the receptor. T cells are sorted to be either helper, cytotoxic, or regulatory variants during maturation, but may differentiate into subsets following T cell activation. Following antigen presentation, the T cell is activated and begins to differentiate. T cell differentiation happens via the following steps:
- The activated T cell becomes a large blast cell.
- The blast cell proliferates by clonal expansion.
- Cloned daughter cells differentiate into either effector T cells or memory T cells.
- Cytotoxic effector T cells are finished, but helper T cells continue to differentiate into individual subsets of helper T cells.
Many different subsets of helper T cells perform various functions. The most common subsets are Th1, which mediates cytotoxic T cell activity through cytokine release, and Th2, which presents antigens to B cells. Additionally, Th17, which only differentiates from effector cells if certain cytokines are present, is important in regulating and inhibiting T-reg cell activity. The effector cells are short-lived for the duration of the adaptive immune response while memory cells are long-lived and are the basis of the secondary immune response.
Specific T-Cell Roles
T helper cells assist the maturation of B cells and memory B cells while activating cytotoxic T cells and macrophages.
Key Points
Helper T cells secrete small proteins called cytokines that regulate or assist in the active immune response by activating other immune cells. They also present antigens to B cells.
Cytotoxic T cells (TC cells, or CTLs) destroy virus-infected cells and tumor cells and are implicated in transplant rejection and autoimmune disease.
Memory T cells persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon re-exposure to their antigens, thus providing the immune system with “memory” against past infections.
Regulatory T cells are crucial for the maintenance of immunological tolerance because they play a role in suppressing overactive immune responses.
Natural killer (NK) T cells bridge the adaptive immune system with the innate immune system by producing cytokines and binding to non-MHC or protein-bound antigens, such as glycolipids and lipids.
Key Terms
- Natural Killer T cells: A heterogeneous group of T cells that shares properties of both T cells and natural killer (NK) cells, and recognizes the non-polymorphic CD1d molecule, an antigen-presenting molecule that binds self- and foreign lipids and glycolipids instead of MHC.
Many different categories and subsets of T cells perform various roles for the immune system. Differentiation for most categories of T cells occurs during the T cell maturation, but memory cell and helper T subset differentiation occurs after maturation following antigen presentation. The different categories of T cells are the basis for cell-mediated immune system activity.
Helper T Cells
Helper T cells assist other white blood cells in immunologic processes by facilitating cytokines that activate and direct other immune cells. Their primary functions include antigen presentation and activation of B cells, and activation of cytotoxic T cells and macrophages. These cells are also known as CD4+ T cells because they express the CD4 protein on their surfaces. Helper T cells become activated when presented with peptide antigens by MHC class II molecules, which are expressed on the surface of antigen-presenting cells. Once activated, they divide rapidly and secrete regulatory cytokines such as IFN-gamma and certain interleukins. These cells can differentiate into one of several subtypes, including TH1, TH2, TH3, TH17, or TFH, which secrete different cytokines to facilitate a different type of immune response. Differentiation into helper T cell subtypes occurs during clonal selection following T cell activation of naive T cells.
Cytotoxic T cells
Cytotoxic T cells (TC cells, or CTLs) destroy virus-infected cells and tumor cells and cause much of the damage in transplant rejection and autoimmune diseases. These cells are also known as CD8+ T cells since they express the CD8 glycoprotein at their surfaces. They recognize their targets by binding to antigens associated with MHC class I, which is present on the surface of nearly every cell of the body. Cytotoxic T cells recognize their antigen on pathogens through their T cell receptor and kill the pathogen through degranulation and cell-mediated apoptosis. The cytotoxic enzymes and proteases travel to their target cells through a microtubule cytoskeleton. Through IL-10, adenosine, and other anti-inflammatory cytokines secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state, which can prevent or reduce the severity of autoimmune diseases.
Memory T Cells
Memory T cells are a subset of antigen-specific T cells that persist long after an infection has resolved. They rapidly proliferate to large numbers of effector T cells upon re-exposure to their antigens, thus providing the immune system with “memory” against past infections. The secondary immune response mediated by memory T cells is much faster and more effective at eliminating pathogens compared to the initial immune response. Memory T cells comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells), which have different properties and release different cytokines. Effector memory cells may be either CD4+ or CD8+ and produce either helper or cytotoxic T cells in a secondary immune response.
Regulatory T Cells
Regulatory T cells (Treg cells), also known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Most Treg cells are CD4+ and arise in the thymus. Naturally-occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX.
Natural Killer T Cells
Natural killer T cells (NKT cells – not to be confused with natural killer cells) bridge the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize peptide antigens presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigen presented by a molecule called CD1d. Once activated, these cells perform functions ascribed to both Th and Tc cells (i.e., cytokine production and release of cytolytic/cell killing molecules). They are also able to recognize and eliminate some tumor cells and cells infected with herpes viruses. They are among the least common type of T cells in the body and are found in the highest density in the liver. There is an association between NKT cell deficiency and the development of autoimmune diseases and chronic inflammatory diseases like asthma, but the exact mechanism of this association is not fully understood.
T cell Activation: T cells become activated upon encountering a pathogen and can become either cytotoxic T or helper T cells.
Active and Passive Humoral Immunity
The humoral immune response is the aspect of immunity mediated by secreted antibodies.
Key Points
Passive immunity is the transfer of active humoral immunity in the form of ready-made antibodies from one individual to another.
Naturally acquired passive immunity includes antibodies given from the mother to her child during fetal development or through breast milk after birth.
Artificially acquired passive immunity is a short-term immunization achieved by the transfer of antibodies and can be administered in several forms.
Active immunity is long-lasting immunity produced by the body’s own immune system and involves the production of long-lasting memory cells.
Active immunity can either be natural, such as from an infection or artificial, such as from vaccination.
Key Terms
- Artificially acquired passive immunity: A short-lived form of immunity gained from the transfer of antibodies produced by another organism.
The humoral immune response (HIR) is the aspect of immunity mediated by secreted antibodies produced by B cells. Secreted antibodies bind to antigens on the surfaces of invading pathogens, which flag them for destruction. Humoral immunity is so named because it involves substances found in the humor or body fluids. There are two types of humoral immunity: active and passive.
Active Humoral Immunity
Active humoral immunity refers to any form of immunity that occurs as a result of the formation of an adaptive immune response from the body’s own immune system. Active immunity is long-term (sometimes lifelong) because memory cells with antigen-binding affinity maturation are produced during the lymphocyte differentiation and proliferation that occurs during the formation of an adaptive immune response. It also refers to the effector functions of antibodies, which include pathogen and toxin neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination.
Active immunity can either be naturally occurring or passive. Natural active immunity generally occurs as a result of infection with a pathogen, in which memory cells that remember the antigen of the infectious agent remain in the body. Artificial active immunity is the result of vaccination. During vaccination, the body is exposed to a weakened form of a pathogen that contains the same antigens as the live pathogen, but cannot mount an infection against the body in its weakened state. Vaccinations have become an effective form of disease prevention that is especially useful in preventing diseases that would normally have a high risk of mortality during infection, where relying on natural active immunity would prove dangerous. However, active immunity does not work to protect against all pathogens, because many can mutate and change their antigen structure over time, which enables them to evade the defenses of immunological memory.
Passive Immunity
Passive immunity is the transfer of active humoral immunity in the form of ready-made antibodies from one individual to another. Passive immunization is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases. Unlike active immunity, passive immunity is short-lived (often only for a few months), because it does not involve the production and upkeep of memory cells.
Passive immunity can occur naturally or artificially. Maternal passive immunity is a type of naturally acquired passive immunity and refers to antibody-mediated immunity conveyed to a fetus by its mother during pregnancy. IgG is passed through the placenta to the developing fetus and is the only antibody isotype that can pass through the placenta. Because passive immunity is short-lived, vaccination is often required shortly the following birth to prevent diseases such as tuberculosis, hepatitis B, polio, and pertussis; however, maternal antibodies can inhibit the induction of protective vaccine responses throughout the first year of life. This effect is usually overcome by secondary responses to booster immunization. Passive immunity is also provided through the transfer of IgA antibodies found in breast milk, which are transferred to the gastrointestinal tract of the infant, protecting against bacterial infections until the newborn has produced enough matured B cells to synthesize its own antibodies.
Artificially-acquired passive immunity is a short-term immunization achieved by the transfer of antibodies, and can be administered in several forms: as human or animal blood (usual horse) plasma or serum, as pooled human immunoglobulin for intravenous (IVIG) or intramuscular (IG) use, and as monoclonal antibodies (MAb). Passive transfer is used to help treat those with immunodeficiency and for several types of severe acute infections that have no vaccine, such as the Ebola virus. Immunity derived from passive immunization lasts for only a short period of time, and there is a potential risk for hypersensitivity reactions and serum sickness, especially from gamma globulin of non-human origin. Passive immunity provides immediate protection, but the body does not develop memory; therefore, the patient is at risk of being infected by the same pathogen later.
Innate and adaptive immunity in the immune system: This chart depicts the different divisions of immunity, including adaptive, innate, natural, artificial, passive (maternal), active (infection), passive (antibody transfer) and active (immunization).
While the immune system is meant to protect the individual against threats, at times an exaggerated immune response generates a reaction against self-antigens leading to autoimmunity. Also, the immune system is not able to defend against all threats at all times.
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Transplantation rejections are immune-mediated responses, represent a hindrance to transplantation
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The etiology of many autoimmune disorders is obscure – the reality is that the prevalence of these disorders increases and manifests more aggressively
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Type-I hypersensitivity disorders are immune-mediated and include allergic bronchial asthma, food allergy, and anaphylactic shock
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Immunodeficiency disorders are rare, but they affect some children
Vaccination is required to induce an adequate active immune response to specific pathogens:
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Live attenuated vaccines: Induce both humoral and cellular response. Contraindicated in pregnancy and immunocompromised states. Examples include adenovirus, Polio (Sabin), Varicella, Smallpox, BCG, Yellow fever, Influenza (intranasal), MMR, Rotavirus, etc
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Killed or inactivated vaccines: Induce only humoral response. Examples include rabies, influenza (injection), Polio (Salk), Hepatitis A, etc
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Subunit vaccines: Examples include HBV, HPV (types 6,11,16 and 18), acellular pertussis, Neisseria meningitides, Streptococcus pneumonia, Hemophilus influenza type b, etc
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Toxoid vaccine: Examples include Clostridium tetani, Corynebacterium diphtheria, etc.
Cellular
Cells of the innate immunity are:
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Phagocytes (monocytes, macrophages, neutrophils, and dendritic cells)
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Natural killer (NK) cells
Cells of the adaptive response are:
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T Lymphocytes classified as CD4+T cells and CD8+T cells
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B Lymphocytes differentiate into plasma cells, which produce specific antibodies
Organ Systems Involved
The organ systems involved in the immune response are primarily lymphoid organs which include, spleen, thymus, bone marrow, lymph nodes, tonsils, and liver. The lymphoid organ system classifies according to the following:
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Primary lymphoid organs (thymus and bone marrow), where T and B cells first express antigen receptors and become mature functionally.
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Secondary lymphoid organs like the spleen, tonsils, lymph nodes, the cutaneous and mucosal immune system; this is where B and T lymphocytes recognize foreign antigens and develop appropriate immune responses.
T lymphocytes mature in the thymus, where these cells reach a stage of functional competence while B lymphocytes mature in the bone marrow the site of generation of all circulating blood cells. Excessive release of cytokines stimulated by these organisms can cause tissue damage, such as endotoxin shock syndrome.
Function
The immune system responds variedly to different microorganisms often determined by the features of the microorganism. These are some different ways in which the immune system acts
Immune Response to Bacteria
The response often depends on the pathogenicity of the bacteria[rx]:
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Neutralizing antibodies are synthesized if the bacterial pathogenicity is due to a toxin
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Opsonizing antibodies – produced as they are essential in destroying extracellular bacteria
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The complement system is activated especially by gram-negative bacterial lipid layers
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Phagocytes kill most bacteria utilizing positive chemotaxis, attachment, uptake and finally engulfing the bacteria
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CD8+ T cells can kill cells infected by bacteria
Immune Response to Fungi [rx]
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The innate immunity to fungi includes defensins and phagocytes
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CD4+ T helper cells are responsible for the adaptive immune response against fungi
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Dendritic cells secrete IL-12 after ingesting fungi, and IL-12 activates the synthesis of gamma interferon which activates the cell-mediated immunity
Immune Response to Viruses [rx]
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Interferon, NK cells, and phagocytes prevent the spread of viruses in the early stage
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Specific antibodies and complement proteins participate in viral neutralization and can limit spread and reinfection
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Adaptive immunity is of foremost importance in the protection against viruses – these include CD8+ T cells that kill them and CD4+ T cells as the dominant effector cell population in response to many virus infections
Immune response to parasites[rx]
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Parasitic infection stimulates various mechanisms of immunity due to their complex life cycle
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Both CD4+ and CD8+ Cells protect against parasites
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Macrophages, eosinophils, neutrophils, and platelets can kill protozoa and worms by releasing reactive oxygen radicals and nitric oxide
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Increased eosinophil number and the stimulation of IgE by Th-2 CD4+ T cells are necessary for the killing of intestinal worms
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Inflammatory responses also combat parasitic infections
Despite Immune response(s) generated by intact and functional Immune system we still fall sick, and this is often due to evasive mechanisms employed by these microbes. Here are some of those.
Strategies of Viruses to Evade the Immune System
Antigenic variation: It is a mutation in proteins that are typically recognized by antibodies and lymphocytes. HIV continually mutates, thus making it difficult for either the immune system to protect against it and also hinders the development of a vaccine.
By disrupting 2′,5′-oligoadenylate synthetase activity or by the production of soluble interferon receptors viruses disrupt the Interferon response.
By several mechanisms, Viruses affects the expression of MHC molecules.
A virus can infect immune cells: Normal T and B cells are also sites of virus persistence. HIV hides in CD4+T cells and EBV in B cells.
Strategies of Bacteria to Evade the Immune System
Intracellular pathogens may hide in cells: Bacteria can live inside metabolically damaged host leukocytes, and escaping from phagolysosomes (Shigella spp).
Other mechanisms:
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Production of toxins that inhibit the phagocytosis
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They are preventing killing by encapsulation
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The release of catalase inactivates hydrogen peroxide
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They infect cells and then cause impaired antigenic presentation
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The organism may kill the phagocyte by apoptosis or necrosis
Strategies of Fungi to Evade the Immune System
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Fungi produce a polysaccharide capsule, which inhibits the process of phagocytosis and overcoming opsonization, complement, and antibodies
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Some fungi inhibit the activities of host T cells from delaying cell-mediated killing
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Other organisms (e.g., Histoplasma capsulatum) evade macrophage killing by entering the cells via CR3 and them escape from phagosome formation
Strategies of Parasites to Evade the Immune System
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Parasites can resist destruction by complement
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Intracellular parasites can avoid being killed by lysosomal enzymes and oxygen metabolites
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Parasites disguise themselves as a protection mechanism
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Antigenic variation (e.g., African trypanosome) is an essential mechanism to evade the immune system
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Parasites release molecules that interfere with immune system normal function
Mechanism
The most important mechanisms of the immune system by which it generates immune response include:
Macrophages produce lysosomal enzymes and reactive oxygen species to eliminate the ingested pathogens. These cells produce cytokines that attract other leukocytes to the site of infection to protect the body. The innate response to viruses includes the synthesis and release of interferons and activation of natural killer cells that recognize and destroys the virus-infected cells. The innate immunity against bacterial consist of the activation of neutrophils that ingest pathogens and the movement of monocytes to the inflamed tissue where it becomes in macrophages. They can engulf, and process the antigen and then present it to a group of specialized cells of the acquired immune response. Eosinophils protect against parasitic infections by releasing the content of their granules.[rx][rx]
Antibody-dependent cell-mediated cytotoxicity (ADCC): A cytotoxic reaction in which Fc-receptor expressing killer cells recognize target cells via specific antibodies.
Affinity maturation: The increase in average antibody affinity mostly seen during a secondary immune response.
Complement system: It is a molecular cascade of serum proteins involved in the control of inflammation, lytic attack on cell membranes, and activation of phagocytes. The system can undergo activation by interaction with IgG or IgM (classical pathway) or by involving factors B, D, H, P, I, and C3, which interact closely with an activator surface to generate an alternative pathway C3 convertase.
Anergy: It is the failure to induce an immune response following stimulation with a potential immunogen.
Antigen processing: Conversion of an antigen into a form that can be recognized by lymphocytes. It is the initial stimulus for the generation of an immune response.
Antigen presentation: It is a process in which specific cells of the immune system express antigenic peptides in their cell membrane along with alleles of the major histocompatibility complex (MHC) which is recognizable by lymphocytes.
Apoptosis: Programmed cell death involving nuclear fragmentation and the formation of apoptotic bodies.
Chemotaxis: Migration of cells in response to concentration gradients of chemotactic factors.
Hypersensitivity reaction: A robust immune response that causes tissue damage more considerable than the one caused by an antigen or pathogen that induced the response. For instance, allergic bronchial asthma and systemic lupus erythematosus are an example of type I and type III hypersensitivity reactions respectively.
Inflammation: Certain reactions that attract cells and molecules of the immune system to the site of infection or damage. It featured increased blood supply, vascular permeability and increased transendothelial migration of blood cells (leukocytes).
Opsonization: A process of facilitated phagocytosis by deposition of opsonins (IgG and C3b) on the antigen.
Phagocytosis: The process by which cells (e.g., macrophages and dendritic cells) take up or engulf an antigenic material or microbe and enclose it within a phagosome in the cytoplasm.
Immunological tolerance: A state of specific immunological unresponsiveness.
Hypersensitivity Reactions
They are overreactive immune responses to antigens that would not normally cause an immune reaction.
Type 1 hypersensitivity reactions: Initial exposure to the antigen causes stimulates Th2 cells. They release IL-4 leading the B cells to switch their production of IgM to IgE antibodies which are antigen-specific. The IgE antibodies bind to mast cells and basophils, sensitizing them to the antigen.
When the body is exposed to the allergen again, it cross-links the IgE bound to the sensitized mast cells and basophils, causing the degranulation and release of preformed mediators including histamine, leukotrienes, and prostaglandins. This causes systemic vasodilation, bronchoconstriction, and increased permeability of vascular endothelium.
The reaction can be divided into two stages – 1) Immediate, in which release of preformed mediators cause the immune response, and 2) Late-phase response 8-12 hours later, in which the cytokines released in the immediate stage stimulate basophils, eosinophils, and neutrophils even though the allergen is removed.
Type 2 hypersensitivity reactions (Antibody dependant cytotoxic hypersensitivity): Immune response against the antigens present on the cell surface. Antibodies binding to the cell surface, activate the complement system and cause the degranulation of neutrophils and destruction of the cell. Such reactions can be targeted at self or non-self antigens. ABO blood group incompatibility leading to acute hemolytic transfusion reactions is an example of Type 2 hypersensitivity.
Type 3 hypersensitivity reactions are also mediated by circulating antigen-antibody complex that may be deposited in and damage tissues. Antigens in type 3 relations are soluble as opposed to cell-bound antigens in type 2.
Type 4 hypersensitivity reactions (delayed-type hypersensitivity reactions): They are mediated by antigen-specific activated T-cells. When the antigen enters the body, it is processed by antigen-presenting cells and presented together with the MHC II to a Th1 cell. If the T-helper cell has already been sensitized to that particular antigen, it will be stimulated to release chemokines to recruit macrophages and cytokines such as interferon-γ to activate them. This causes local tissue damage. The reaction takes longer than all other types, around 24 to 72 hours.
Transplant Rejection
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Xenografts are grafts between members of different species, triggers the maximal immune response. Rapid rejection.
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Allografts are grafts between members of the same species.
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Autografts are grafts from one part of the body to another. No rejection.
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Isografts are grafts between genetically identical individuals. No rejection.
- Hyperacute Rejection: In hyperacute rejection, the transplanted tissue is rejected within minutes to hours because vascularization is rapidly destroyed. Hyperacute rejection is antibody-mediated and occurs because the recipient has preexisting antibodies against the graft, which can be due to prior blood transfusions, multiple pregnancies, prior transplantation, or xenografts. Activation of the complement system leads to thrombosis in the vessels preventing the vascularization of the graft.
- Acute Rejection: Develops within weeks to months. Involves the activation of T lymphocytes against donor MHCs. May also involve humoral immune response, which antibodies developing after transplant. It manifests as vasculitis of graft vessels with dense interstitial lymphocytic infiltrate.
- Chronic Rejection: Chronic rejection develops months to years after acute rejection episodes have subsided. Chronic rejections are both antibody- and cell-mediated. The use of immunosuppressive drugs and tissue-typing methods has increased the survival of allografts in the first year, but chronic rejection is not prevented in most cases. It generally presents as fibrosis and scarring. In heart transplants, chronic rejection manifests as accelerated atherosclerosis. In transplanted lungs, it manifests as bronchiolitis obliterans. In liver transplants, it manifests as vanishing bile duct syndrome. In kidney recipients, it manifests as fibrosis and glomerulopathy.
- Graft-versus-host Disease: The onset of the disorder varies. Grafted immunocompetent T cells proliferate in the immunocompromised host and reject host cells which they consider ‘nonself’ leading to severe organ dysfunction. It is a type 4 hypersensitivity reaction and manifests as maculopapular rash, jaundice, diarrhea, hepatosplenomegaly. Usually occurs in the bone marrow and liver transplants, which are rich in lymphocytes.
Related Testing
The immunological investigations for the study of innate and adaptive immunity are listed below and include the assessment of immunoglobulins, B and T-lymphocyte counts, lymphocyte stimulation assays, quantification of components of the complement system, and phagocytic activity.[rx][rx][rx][rx][rx]
Quantitative Serum Immunoglobulins
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IgG
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IgM
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IgA
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IgE
IgG Sub-Classes
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IgG1
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IgG2
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IgG3
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IgG4
Antibody Activity
IgG antibodies (post-immunization)
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Tetanus toxoid
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Diphtheria toxoid
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Pneumococcal polysaccharide
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Polio
IgG antibodies (post-exposure)
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Rubella
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Measles
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Varicella Zoster
Detection of isohemagglutinins (IgM)
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Anti-type A blood
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Anti-type B blood
Other assays
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Test for heterophile antibody
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Anti-streptolysin O titer
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Immunodiagnosis of infectious diseases (HIV, hepatitis B, and C, HTLV and dengue)
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Serum protein electrophoresis
Blood Lymphocyte Subpopulations
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Total lymphocyte count
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T lymphocytes (CD3, CD4, and CD8)
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B lymphocytes (CD19 and CD20)
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CD4/CD8 ratio
Lymphocyte Stimulation Assays
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Phorbol ester and ionophore
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Phytohemagglutinin
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Antiserum to CD3
Phagocytic Function
Nitroblue tetrazolium (NBT) test (before and after stimulation with endotoxin)
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Unstimulated
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Stimulated
Neutrophil mobility
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In medium alone
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In the presence of chemoattractant
Complement System Evaluation
Measurement of individuals components by immunoprecipitation tests, ELISA, or Western blotting
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C3 serum levels
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C4 serum levels
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Factor B serum levels
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C1 inhibitor serum levels
Hemolytic assays
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CH50
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CH100
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AH50
Complement system functional studies
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Classical pathway assay (using IgM on a microtiter plate)
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Alternative pathway assay (using LPS on a microtiter plate)
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Mannose pathway assay (using mannose on a microtiter plate)
Measurement of complement-activating agents
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Circulating immune complexes
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Cold agglutinins
Assays for complement-binding
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C1q autoantibody ELISA
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C1 inhibitor autoantibody ELISA
Others complement assays
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LPS activation assay
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Specific properdin test
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C1 inhibitor activity test
Autoimmunity Studies
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Anti-nuclear antibodies (ANA)
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Detection of specific auto-immune antibodies for systemic disorders (anti-ds DNA, rheumatoid factor, anti-histones, anti-Smith, anti-(SS-A) and anti-(SS-B)
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Detection of anti-RBC, antiplatelet, and anti-neutrophil
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Testing for organ-specific auto-immune antibodies
Microbiological Studies
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Blood (bacterial culture, HIV by PCR, HTLV testing)
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Urine (testing for cytomegalovirus, sepsis, and proteinuria)
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Nasopharyngeal swab (testing for Rhinovirus)
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Stool (testing for viral, bacterial or parasitic infection)
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Sputum (bacterial culture and pneumocystis PCR)
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Cerebrospinal fluid (culture, chemistry, and histopathology)
Coagulation Tests
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Factor V assay
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Fibrinogen level
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Prothrombin time
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Thrombin time
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Bleeding time
Other Investigations
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Complete blood cell count
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Tuberculin test
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Bone marrow biopsy
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Histopathological studies
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Liver function test
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Blood chemistry
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Tumoral markers
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Serum levels of cytokines
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Chest x-ray
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Diagnostic ultrasound
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CT scan
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Fluorescent in situ hybridization (FISH)
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DNA testing (for most congenital disorders)
Pathophysiology
The immune system protects the body against many diseases including recurrent infections, allergies, tumors, and autoimmunity. The consequences of an altered immunity will manifest in the development of many immunological disorders some of which are listed below:
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X- linked agammaglobulinemia (Bruton disease)
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Selective IgA Deficiency
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Selective IgG deficiency
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Congenital thymic aplasia (DiGeorge Syndrome)
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Chronic mucocutaneous candidiasis
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Hyper-IgM syndrome
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Interleukin-12 receptor deficiency
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Severe combined immunodeficiency disease (SCID)
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ZAP-70 deficiency
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Janus kinase 3 deficiency
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RAG1 and RAG2 deficiency
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Wiskott-Aldrich syndrome
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Immunodeficiency with ataxia-telangiectasia
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MHC deficiency (bare leukocyte syndrome)
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Complement system deficiencies
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Hereditary angioedema
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Chronic granulomatous disease (CGD)
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Leukocyte adhesion deficiency syndrome
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Job syndrome
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Chediak Higashi syndrome
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Acquired immunodeficiency syndrome
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Anaphylaxis
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Allergic bronchial asthma
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Allergic rhinitis
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Allergic conjunctivitis
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Food allergy
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Atopic eczema
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Drug allergy
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Immune thrombocytopenia
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Autoimmune hemolytic anemia
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Autoimmune neutropenia
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Systemic lupus erythematosus
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Rheumatoid arthritis
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Autoimmune hepatitis
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Hemolytic disease of the fetus and the newborn (erythroblastosis fetalis)
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Myasthenia gravis
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Goodpasture syndrome
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Pemphigus
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Tuberculosis
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Contact dermatitis
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Leprosy
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Insulin-dependent diabetes mellitus
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Schistosomiasis
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Sarcoidosis
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Crohn disease
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Autoimmune lymphoproliferative syndrome
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X-linked lymphoproliferative disorder
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Common variable immunodeficiency
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B-cell chronic lymphocytic leukemia
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B-cell prolymphocytic leukemia
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Non-Hodgkin lymphoma (including mantle cell lymphoma) in leukemic phase
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Hairy cell leukemia
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Multiple myeloma
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Splenic lymphoma with villous lymphocytes
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Sezary syndrome
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T-cell prolymphocytic leukemia
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Adult T-cell leukemia-lymphoma
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Large granulated lymphocyte leukemia
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Leukocyte adhesion deficiency syndrome
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Chronic active hepatitis
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Coccidioidomycosis
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Behcet disease
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Aphthous stomatitis
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Familial keratoacanthoma
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Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy
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Idiopathic CD4+ lymphocytopenia
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Complement system deficiencies
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ADA-SCID
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Artemis SCID
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Newly diagnosed non-germinal center B-cell subtype of diffuse large B-cell lymphoma
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Melanoma
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Chagas disease
References