Becky model questions Flashcards
(21 cards)
Describe the sequence of cellular interactions that lead to the sensitisation of mast cells and subsequent IgE-mediated allergic response.
The IgE-mediated allergic response, or Type 1 hypersensitivity, involves a complex series of cellular interactions culminating in mast cell sensitisation and subsequent allergic reactions. This essay outlines the key steps in this immunological process.
The allergic response begins when an individual is first exposed to an allergen e.g., pollen, dustmites. The allergen is processed by antigen-presenting cells (APCs), such as dendritic cells or macrophages, which present allergenic peptides on MHC class II molecules to naive T-helper cells.
In susceptible individuals, APCs induce differentiation of naive T helper cells into Th2 cells. This differentiation is influenced by cytokines such as IL-4. Th2 cells secrete cytokines, notably IL-4, IL-5, and IL-13, which are crucial in the allergic response. IL-4 and IL-13 promote the activation of allergen-specific B cells. These B cells interact with Th2 cells through CD40-CD40L signalling. B cells undergo class switching to produce IgE antibodies specific to the allergen, a process driven by IL-4. The activated B cells differentiate into plasma cells, secreting large quantities of allergen-specific IgE.
The secret IgE binds to high-affinity IgE receptors on the surface of mast cells and basophils. This binding sensitises these cells to the allergen.
On subsequent exposure, the allergen cross-links the IgE molecules bound to high-affinity IgE receptors on sensitised mast cells. This crosslinking triggers mast cell degranulation, releasing pre-formed mediators such as histamine, proteases, and cytokines.
Histamine causes vasodilation, increased vascular permeability, and smooth muscle contraction, leading to symptoms such as urticaria, angioedema, bronchoconstriction and anaphylaxis.
Cytokines and chemokines released during degranulation recruit other immune cells, such as eosinophils and neutrophils, contributing to the late-phase allergic response with pro-longed inflammation and tissue damage.
Conclusion: The IgE-mediated allergic response involves a well-coordinated series of cellular interactions, beginning with allergen recognition, B-cell activation, and mast cell sensitisation, culminating in the degranulation of mast cells upon re-exposure to the allergen. This complex process underlies the pathophysiology of allergic reactions, highlighting potential targets for therapeutic intervention in allergic diseases.
Describe the cells and mediators in an allergic response.
An allergic response, or Type 1 hypersensitivity, is an exaggerated immune reaction to harmless allergens. This essay outlines the key cells and mediators involved in this complex immune response.
A key cell involved in allergic response are mast cells. Central to the allergic response, they contain granules filled with pre-formed mediators like histamine. They are sensitised by IgE bound to FcεRI receptors. Upon allergen exposure, they degranulate, releasing mediators that cause acute allergic symptoms.
Basophils are circulating counterparts of mast cells with similar functions. They release histamine and other mediators upon activation, contributing to the inflammatory response. Eosinophils are involved in the late-phase allergic response and chronic inflammation. Recruited by cytokines like IL-5, eosinophils release toxic granules and inflammatory mediators, exacerbating tissue damage.
T-helper 2 (Th2) cells orchestrate the allergic response by secreting cytokines such as IL-4, IL-5, and IL-13, promoting IgE production and eosinophil recruitment. They are activated by antigen-presenting cells presenting allergens.
B cells and Plasma cells are responsible for producing allergen-specific IgE antibodies. They are stimulated by Th2 cytokines and undergo class switching to secrete IgE.
Antigen-presenting cells include dendritic cells and macrophages, which capture and present allergens to naive T cells, initiating the immune response.
There are also several key mediators of allergic response.:
Histamine is released from mast cells and basophils during degranulation. It causes vasodilation, increased vascular permeability, bronchoconstriction, and itching, leading to symptoms like urticaria, edema, and bronchospasm.
Leukotrienes such as LTC4, LTD4, and LTE4 are synthesised by mast cells and eosinophils. They prolong bronchoconstriction, increase mucus secretion, and promote vascular permeability, contributing to sustained inflammation.
Prostaglandins (e.g., PGD2) are produced by mast cells. They enhance vasodilation, bronchoconstriction, and recruit inflammatory cells.
Cytokines (e.g., IL-4, IL-5, and IL-13) are secreted by Th2 cells and mast cells. IL-4 promotes IgE class switching, IL-5 recruits and activates eosinophils, and IL-13 enhances mucus production and airway hyperresponsiveness.
Chemokines attract immune cells to the site of allergen exposure, facilitating inflammation and tissue damage.
Platelet-activating factor is released by various cells, including mast cells. They induce platelet aggregation, bronchoconstriction, and increased vascular permeability.
Conclusion: The allergic response is mediated by a diverse array of cells and chemical mediators. Mast cells and basophils initiate the acute response, while eosinophils, Th2 cells, and various cytokines sustain the inflammatory process. Understanding these components is crucial for developing target therapies for allergic diseases.
a) Describe the role of antibodies and mast cells as mediators of an allergic response [12.5 marks]
b) Discuss the genetic and environmental factors impacting allergy [12.5 marks]
a) In allergic individuals, allergen exposure triggers B cells to produce allergen-specific IgE antibodies, facilitated by Th2 cells and cytokines like IL-4. IgE binds to high-affinity FcεRI receptors on mast cells and basophils, sensitising these cells to future allergen exposure.
Upon subsequent allergen exposure, crosslinking of IgE on sensitised mast cells occurs, leading to mast cell activation. Activated mast cells release pre-formed mediators such as histamine, proteases, and cytokines. Histamine is a major mediator causing vasodilation, increased vascular permeability and bronchoconstriction. This degranulation results in acute allergic symptoms such as itching, swelling and airway constriction (e.g., in asthma or anaphylaxis). Mast cells also release cytokines that recruit other inflammatory cells, contributing to prolonged allergic inflammation.
b) Genetic factors: A strong familial component is observed in allergic diseases. If one or both parents have allergies, the risk for the child increases. Variations in genes encoding cytokines (e.g., IL-4, IL-5 and IL-13) and IgE receptors influence susceptibility to allergies. Genetic predisposition to produce higher levels of IgE in response to allergens is also a key factor in allergic diseases.
Environmental factors: early exposure to allergens, microbial diversity, and infections can influence immune system development and allergy risk. Early introduction or avoidance of certain foods may impact the development of food allergies. Environmental pollutants and tobacco smoke can exacerbate allergic diseases by enhancing airway inflammation and sensitisation. Certain occupations expose individuals to allergens, e.g., latex, and increase the risk of sensitisation. Changes in pollen seasons and allergen distribution due to climate change can impact the prevalence and severity of allergic diseases.
Environmental factors can also modify gene expression through epigenetic mechanisms, influencing the immune response and allergy risk. Individuals with genetic susceptibility may respond more strongly to environmental exposures, increasing the likelihood of developing allergies.
Conclusion: both antibodies (IgE) and mast cells play pivotal role in mediating allergic responses, leading to characteristic symptoms. Genetic predisposition and environmental factors interact to influence the development and severity of allergic diseases, highlighting the complexity of allergy etiology.
Explain the roles of direct and indirect allorecognition in solid organ transplant rejection.
Solid organ transplantation is often complicated by immune responses against donor antigens, leading to rejection. The immune system recognises these foreign antigens via direct and indirect allorecognition pathways. This essay explains the mechanisms and their roles in transplant rejection.
In direct allorecognition, recipient T cells recognise intact donor Major Histocompatibility Complex (MHC) molecules presented on the surface of donor antigen-presenting cells, such as dendritic cells, that are present in the graft. CD8+ T cells recognise donor MHC class I molecules, leading to cytotoxic T-cell responses and direct killing of donor cells.
CD4+ T cells recognise donor MHC class II molecules, resulting in the activation of helper T cells, which produce cytokines that stimulate other immune cells.
Direct allorecognition is critical in the early phase of acute rejection. The rapid and strong T-cell response leads to inflammation, graft damage, and loss of graft function.
In indirect allorecognition, recipient APCs process and present donor-derived peptides (allogenic MHC) on self-MHC molecules to recipient T cells. CD4+ T cells are primarily involved in recognising processed donor antigens presented by recipient APCs. This leads to a more prolonged immune response.
Indirect allorecognition is more associated with chronic rejection. It contributes to sustained immune activation, leading to chronic inflammation, fibrosis, and gradual loss of graft function.
In humoral immunity, indirect pathway also facilitates B-cell activation and the production of donor-specific antibodies, contributing to antibody-mediated rejection.
Direct allorecognition dominates the acute phase of rejection, while indirect allorecognition plays a significant role in chronic rejection. Both pathways can operate simultaneously, with direct allorecognition driving initial graft damage and indirect pathways sustaining the immune response over time.
Conclusion:Direct and indirect allorecognition pathways are central to the immune response in solid organ transplant rejection. Direct allorecognition primarily drives acute rejection whereas indirect allorecognition contributes to chronic rejection and long-term graft loss. Understanding these mechanisms is essential for developing targeted immunosuppressive therapies to improve graft survival.
Explain direct and indirect allorecognition by T-cells and the role of alloreactive T-cells in solid organ graft rejection.
Solid organ transplant rejection occurs when the recipients immune system recognises the donor tissue as foreign. T-cells play a pivotal role in this process through direct and indirect allorecognition. This essay explores these pathways and their impact on graft rejection.
In direct allorecognition, recipient T-cells recognise intact, unprocessed donor MHC molecules presented on the surface of donor antigen-presenting cells in the graft. CD8+ T cells recognise donor MHC I molecules, leading to the activation of cytotoxic T-cells that directly kill donor cells. CD4+ T cells recognise donor MHC II molecules, resulting in helper T-cell activation, which amplifies the immune response by releasing cytokines. Direct allorecognition is primarily involved in acute rejection, causing rapid inflammation, cytotoxicity, and tissue damage.
In indirect allorecognition, recipient APCs process donor-derived antigens and present these peptides on self-MHC molecules to recipient T-cells. CD4+ T cells recognise processed donor antigens presented by recipient APCs, leading to T-cell activation and recruitment of additional immune cells. Indirect allorecognition is more associated with chronic rejection, characterised by sustained immune responses, fibrosis, and gradual graft deterioration. It also facilitates the production of donor-specific antibodies by B-cells, contributing to antibody-mediated rejection.
Both pathways lead to the proliferation of alloreactive T cells, which are critical for graft rejection. CD8+ alloreactive T-cells directly attack and kill donor cells, contributing to acute rejection. CD4+ alloreactive T-cells produce cytokines like IL-2, which recruit and activate other immune cells, amplify the immune response and help B-cells produce antibodies. Sustained activity of alloreactive T-cells leads to chronic inflammation, promoting fibrosis and vascular damage in the graft, culminating in chronic rejection.
Conclusion: Direct and indirect allorecognition by T-cells are central to solid organ graft rejection. Direct allorecognition primarily derives acute rejection, while indirect allorecognition plays a significant role in chronic rejection and long-term graft failure. Alloreactive T-cells, through their cytotoxic and helper functions, are key mediators in both acute and chronic rejection processes, underscoring their importance in the immunological response to transplants.
Explain the three ways in which solid organ transplants can be rejected by the recipient.
Solid organ transplant rejection occurs when the recipients immune system identifies the transplanted organ as foreign and mounts an immune response. There are three main types of rejection: hyperacute, acute, and chronic. This essay explores each type, including their mechanisms and clinical implications.
Hyperacute rejection occurs within minutes to hours of transplantation. It is mediated by pre-existing antibodies in the recipient that recognise donor antigens, primarily on endothelial cells, leading to complement activation. The rapid binding of antibodies to donor antigens activates the complement system, resulting in endothelial damage, inflammation and thrombosis. The graft becomes swollen, cyanotic, and rapidly fails. It is irreversible and requires immediate removal of the graft. It often results from mismatched blood types or prior sensitisation to donor antigens due to previous transplant, blood transfusion, or pregnancies.
Acute rejection occurs within days to weeks after transplantation and is mediated by the recipients T-cells recognising donor antigens through direct or indirect allorecognition. T-cell mediated cytotoxicity directly attacks graft cells, causing inflammation and tissue damage. B-cell activation leads to the production of donor-specific antibodies, which bind to graft antigens, activating complement and promoting inflammation. Symptoms of acute rejection include graft tenderness, reduced organ function, and signs of systemic inflammation. Acute rejection is potentially reversible with prompt immunosuppressive therapy.
Chronic rejection develops over months to years and involves both cellular and antibody-mediated immune responses. It is characterised by chronic inflammation, fibrosis, and vascular changes. Persistent low-grade immune responses lead to graft arteriosclerosis, fibrosis, and gradual loss of graft function. Manifests as progressive decline in organ function, with symptoms depending on the affected organ- e.g., renal dysfunction in kidney transplants. Chronic rejection is often irreversible and a major cause of long-term graft failure despite ongoing immunosuppresive therapy.
Conclusion: The 3 types of transplant rejection differ in their onset, mechanisms, and clinical outcomes. Hyperacute rejection is immediate and antibody-mediated, acute rejection involves both T-cells and antibodies, and chronic rejection is characterised by long-term immune responses leading to fibrosis and organ failure. Understanding these mechanisms is crucial for the management and improvement of transplant outcomes.
Describe the immunological processes that are involved in the pathology of systemic lupus erythematosus (SLE)
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterised by a loss of immune tolerance, leading to widespread inflammation and tissue damage. This essay outlines the key immunological processes involved in SLE.
Genetic factors, such as polymorphisms in HLA genes, contribute to defective immune regulation. Failure in central and peripheral tolerance mechanisms allows autoreactive B and T cells to persist. Autoreactive B cells produce antibodies, particularly anti-nuclear antibodies (ANAs) and anti-double-stranded-DNA antivodies. Autoantibodies form immune complexes with self-antigens, which deposit in tissues and activate the complement system, contributing to inflammation and tissue damage.
Abnormal activation of helper T cells supports the activation of autoreactive B cells. Dysfunctional Tregs fail to suppress autoreactive immune cells, exacerbating the autoimmune response.
Immune complexes activate the complement system, leading to the formation of C3 and C5a, which promote inflammation and recruitment of neutrophils and macrophages. Complement activation contributes to tissue injury in organs like the kidneys (lupus nephritis), skin and joints.
Elevated levels of cytokines such as IL-6, IL-17, TNF-a and IFN-a drive inflammation. Increased expression of type I interferons, IFN-a, enhances the activation of dendritic cells, promoting further autoreactive T and B cell responses.
Defective clearance of apoptotic cells result in the accumulation of cellular debris, providing a continuous source of self-antigens. Dendritic cells present auto-antigens to T cells, perpetuating the autoimmune response.
Chronic immune activation leads to inflammation and damage in multiple organs, including the kidneys, skin, joints, heart and central nervous system. Symptoms may vary widely and can include fatigue, joint pain, skin rashes, and organ dysfunction, depending on the extent of immune complex deposition.
Conclusion: The pathology of SLE involves a complex interplay of genetic predisposition, loss of immune tolerance, autoantibody production, immune complex deposition, complement activation, and chronic inflammation. These processes collectively result in the diverse clinical manifestations of SLE. Understanding these mechanisms is crucial for developing targeted therapies to manage this autoimmune disease.
Give the definition of an autoimmune disease [5 marks]
And
Describe a named autoimmune disease including:
The primary tissue affected
* The immune-pathogenesis of the disease
* The main clinical features
[15 marks]
a) An autoimmune disease is a condition in which the immune system mistakenly attacks the body’s own tissues, recognising self-antigens as foreign and mounting an immune response against them. This leads to inflammation, tissue damage, and dysfunction of the affected organs. The parts of the body affected depend on which autoimmune disease a person has. Typical examples of autoimmune diseases include Rheumatoid arthritis, Inflammatory bowel disease, and Systemic Lupus Erythematosus.
b) Systemic Lupus Erythematosus is an example of a systemic autoimmune disease that can affect multiple tissues and organs, including the skin, joints, kidneys, heart, lungs and central nervous system.
Genetic predisposition and environmental triggers such as UV light or infections, contribute to the loss of tolerance, leading to autoreactive immune cells.
Failure to clear apoptotic cells exposes nuclear antigens to the immune system. APCs internalise the nuclear antigens and present the antigen to nuclear self-antigen autoreactive CD4+ T-cells.
CD4+ T-cells provide help to B-cells which produce large quantities of self reactive antibodies.
These autoantibodies form immune complexes with self-antigens.
Immune complexes deposit in tissues such as kidneys or skin, activating the complement system and triggering an inflammatory response.
Elevated cytokines, including type I interferons (IFN-a) amplify the immune response and contribute to tissue damage. Impaired clearance of apoptotic cells results in the persistence of self-antigens, perpetuating the autoimmune response, leading to tissue damage.
Main clinical features include butterfly-shaped rash across the cheeks and nose, photosensitivity and discoid lesions. Typically non-erosive arthritis affects multiple joints. In the kidneys presents as Lupus nephritis characterised by proteinuria, hematuria and possible renal failure. Systemic symptoms include fatigue, fever and weight loss. SLE may also present neuropsychiatric symptoms such as seizures or psychosis.
Conclusion: Systemic Lupus Eryhtematosus is a complex autoimmune disease involving multiple organs, driven by autoantibody production and immune complex deposition. Early diagnosis and management with immunosuppresive therapies are crucial to prevent organ damage and improve outcomes.
Discuss how the immune system recognises tumour cells.
The immune system plays a critical role in recognising and eliminating tumour cells. This process involves both innate and adaptive immune responses that detect tumour-specific and tumour-associated antigens. This essay outlines the mechanisms by which the immune system recognises tumour cells, focusing on key components and pathways involved.
Tumour-specific antigens are unique to tumour cells and result from mutations in oncogenes or tumour suppressor genes. Examples include mutated p53 and abnormal fusion proteins like BCR-ABL. Tumour-associated antigens are expressed at higher levels or abnormally by tumour cells compared to normal cells. Examples include HER2/neu in breast cancer and carcinoembryonic antigen in colorectal cancer.
Natural Killer cells recognise and kill tumour cells with reduced or absent MHC class I molecules, a common feature of many tumours. NK cells use activating receptors like NKG2D to detect stress-induced ligands, e.g., MICA/MICB, on tumour cells.
Macrophages and dendritic cells recognise tumour cells through pattern recognition receptors (PRRs) like toll-like receptors (TLRs). They engulf tumour cells and present antigens to T cells, linking innate and adaptive immunity.
Tumour antigens are processed by antigen-presenting cells like dendritic cells and presented on MHC I molecules to CD8+ cytotoxic T lymphocytes. CD8+ T cells recognise tumour antigens presents by MHC I and initiate a targeted immune response by releasing perforin and granzymes, inducing apoptosis in tumour cells. CD4+ helper T cells recognise tumour antigens presented on MHC II by APCs, proving essential cytokine support, e.g., IL-2, for the activation and proliferation of CD8+ T cells and B cells.
Tumour cells exploit immune check points, such as PD-1/PD-L1 and CTLA-4 pathways, to evade immune detection. By expressing PD-L1, tumours cells inhibit T-cell activity, promoting immune evasion. Tumours also create an immunosuppressive microenvironment by recruiting regulatory T cells (Tregs) and myeloid-derived suppressor cells, which secret immunosuppressive cytokines (e.g., IL-10, TGF-Beta).
The immune system continuously monitors for and eliminates emerging tumour cells. Failure in this process can lead to tumour progression. Immunoediting involves three phrases- elimination of tumour cells, equilibrium control of tumour growth and and tumour evasion of the immune system.
Conclusion: The immune system recognises tumour cells through tumour-specific and tumour-associated antigens, employing both innate and adaptive mechanisms. Despite its efficacy, tumours can evade immune detection through various mechanisms, necessitating the development of immune-based therapies like immune checkpoint inhibitors to enhance anti-tumour responses.
Discuss the mechanisms by which tumours are able to escape immune recognition.
Tumours can evade immune recognition through several mechanisms, allowing them to grow and spread despite the immune system’s surveillance. The main mechanisms include immunoediting and tumour heterogenity.
Tumours under immunoediting, a process where immune cells selectively eliminate sensitive clones, leaving behind resistant variants. Over time, this results in immune-resistant tumour clones, contributing to tumour heterogenity. Tumours evolve to escape immune detection by expressing different antigens or mutating genes involved in immune recognition.
Tumours can also create an immunosuppressive microenvironment by secreting cytokines (e.g., TGF-Beta, IL-10), attracting regulatory T cells (Tregs) and myeloid-derived suppressor cells. These cells inhibit effective immune responses, suppressing cytotoxic T lymphocyte activity and promoting immune tolerance.
Tumours often downregulate or loss the expression of major histocompatibility complex (MHC) class I molecules, which are essential antigen presentation to CD8+ T cells. Without this presentation, tumours cells escape detection by cytotoxic T cells. Some tumours also express alternative MHC molceules or immunosuppressive ligands, like PD-L1, which inhibit T cell activation.
Tumour cells frequently express immune checkpoint ligands such as PD-L1 and CTLA-4. These ligands bind to corresponding receptors on T cells, leading to T cell exhaustion and an inability to mount an effective immune response.
Chronic antigen stimulation can result in T cell exhaustion, a state where T cells become anergic and lose their cytotoxic function. Tumours can induce this through persistent expression of immune checkpoint ligands, leading to a suppressed immune response.
Tumour cells secrete factors like IL-10 and TGF-Beta, which inhibit immune responses by suppressing T cell activation and promoting the development of immune-tolerant cells like Tregs. These factors also prevent the recruitment and activation of immune effector cells.
Some tumours can down regulate or mutate the expression of tumour-associated antigens or neoantigens, which are recognised by the immune system. This prevents the immune system from identifying and targeting tumour cells effectively.
Tumours can alter their antigenic profile by undergoing somatic mutations, leading to a loss of recognisable antigens. This form of antigenic variation allows tumours cells to avoid recognition by the immune system, especially by adaptive immune cells.
Conclusion: Tumours utilise a multifaceted approach to escape immune recognition, including the creation of immunosuppresive environments, alterations in antigen presentation, and the activation of immune checkpoints. These strategies ensure tumour persistence, complicating the effectivness of immune-based therapies.
The immune system is important in the recognition and elimination of cancer cells.
a. Explain the how tumour cells are recognised and eliminated by cytotoxic T-cells [5 marks]
b. Discuss the mechanisms by which tumours are able to escape immune recognition by cytotoxic T-cells [20 marks]
a) Tumour cells often express as tumour-associated antigens or neoantigens, which are abnormal proteins resulting from mutations. These antigens are processed and presented on the surface of tumour cells by MHC I molecules. Cytotoxic T cells have T cell receptors that recognise and bind to presented antigens on MHC I molecules of tumour cells. When a cytotoxic t cell recognises a tumour-specific antigen, it becomes activated. The activation involves co-stimulatory signals provided by antigen presenting cells and cytokines like IL-2. Once activated cytotoxic t cells release cytotoxic molecules such as perforin and granzymes which induce apoptosis in tumour cell. perforin creates pores in the tumour cell membrane, allowing granzymes to enter and trigger cell death. After eliminating tumour cells, cytotoxic t cells can differentiate into memory t cells, providing long term immunity against recurrence of tumour.
b) summarised:
Loss of MHC I molecules
Immune checkpoint activation
T-cell exhaustion
Immunosuppressive cytokines
Tregs
Myeloid-derived suppressor cells
Antigenic variation
soluble immunosuppressive factors
molecular mimicry of self antigens
altered antigen processing
Discuss the immunotherapeutic treatment strategies to treat cancer.
Immunotherapy harnesses the body’s immune system to fight cancer. various strategies have been developed to treat cancer by boosting immune responses or correcting immune evasion mechanisms.
Checkpoint inhibitor drugs block immune checkpoint molecules such as PD-1, PD-L1, and CTLA-4, that inhibit T cell activity. Examples: Pembrolizumab- PD-1 inhibitor, Nivolumab PD-1 inhibitor and Ipilimumab CTLA-4 inhibitor. These increase T cell activation, enhancing the immune response against cancer cells.
Monoclonal antibodies target specific tumour antigens, marking cancer cells for destruction by immune cells or blocking tumour growth signals. Rituximab targets CD20 in B cell lymphoma, and trastuzumab targets HER2 in breast cancer. These can induce direct cell killing, inhibiting tumour growth or enhance immune recognition.
Cancer vaccines aim to stimulate the immune system to recognise and attack cancer-specific antigens or neoantigens. Preventive vaccines like HPV vaccine and therapeutic vaccines like Sipuleucel-T for prostate cancer, induces long-lasting immunity and reduces recurrence risk.
Adoptive cell transfer involves T cells being extracted from a patient, modified or expanded ex vivo and reinfused into the patient. E.g., Kymriah CAR-T for leukemia. Outcome is enhance tumour targeting by engingeered T cells capable of recognising and killing cancer cells.
Oncolytic virus therapy involves oncolytic viruses selectively infecting and killing cancer cells while sparing normal cells. These viruses can also stimulate immune responses by releasing tumour antigens. E.g., T-VEC is a modified herpesvirus for melanoma. Outcome is direct tumour destruction and immune system activation against tumour.
Immune system modulator therapy enhance the overall immune response, increasing the effectiveness of the immune system in fighting cancer. e.g., interleukins IL-2 and interferons stimulate t-cell and natural killer cell activity to fight tumours.
Discuss the role of MHC II and co-stimulatory molecules presented by dendritic cells in the generation of CD4+ T-cell response to a pathogen.
The generation of a CD4+ T cell response to a pathogen relies heavily on the interaction between dendritic cells, MHC II and co-stimulatory molecules. Dendritic cells play crucial role in initiation of adaptive immune responses by presenting antigens to naive CD4+ T cells.
Dendritic cells as APCs, capture pathogens through phagocytosis or endocytosis. after pathogen uptake, dendritic cells process pathogen into small peptides with their endosomal compartments.
Processed antigenic peptides are loaded onto MHC II molecules in the endosome. Upon activation by pathogen-associated signals, dendritic cells migrate from peripheral tissues to lymph nodes. In lymph nodes, dendritic cells present antigen MHC II complexes on their surface to naive CD4+ T cells.
T cell receptor on CD4+ T cells recognises and binds to the peptide MHC II complex on dendritic cells surface. This interaction ensures that only CD4+ t cells with TCRs specific for presented peptide are activated ensuring specificity in immune response.
In addition to MHC II-TCR interaction, dendritic cells express co-stimulatory molecules CD80/CD86 that bind to CD28 on CD4+ T cells. The engagement of CD28 provides necessary secondary signal for T cell activation, ensuring the T cell does not become anergic.
Succesfful activation of CD4+ T cell requires both the antigenic signal and the co-stimulatory signal. Dendritic cells secrete cytokines IL-12 and IL-6 that influence the differentiation of CD4+ T cells into specific subsets, such as Th1 , Th2, or Th17 based on pathogen types.
Activated CD4+ T cells undergo clonal expansion, increasing their number to mount an effective immune response. Differentiated CD4+ T cells help coordinate immune responses by releasing cytokines,activating B cells, macrophages and other immune cells or aiding in activation of CD8+ T cells.
Briefly explain the role of dendritic cells during the priming of CD4+ and CD8+ T-cell responses.
Dendritic cells are central to priming of both CD4+ and CD8+ T-cell responses. Their key role is in capturing, processing, and presenting antigens, as well as providing co-stimulatory signals that are essential for the activation and differentiation of T-cells. The priming process differs slightly between CD4+ and CD8+ T-cells, but the fundamental mechanisms are similar.
Dendritic cells capture pathogens or tumour antigens via phagocytosis, endocytosis or macropinocytosis. Dendritic cells process captured antigens into peptide fragments within endosomal or lysosomal compartments.
Upon encountering pathogens or inflammatory signals, dendritic cells mature and migrate from peripheral tissues (e.g., skin, mucosal surfaces) to secondary lymphoid organs (e.g., lymph nodes).
In the lymph nodes, dendritic cells upregulate MHC molecules, co-stimulatory molecules (e.g., CD80, CD86), and cytokine production, crucial for T-cell activation.
Dendritic cells present processed antigen peptides on MHC II molecules to naive CD4+ T cells. Co-stimulatory molecules on dendritic cells bind to CD28 on CD4+ T cells providing the second activation signal. DCs secrete cytokines (e.g., IL-12, IL-6) that influence the differentiation of CD4+ T-cells into specific subsets (e.g., Th1, Th2, Th17).
Dendritic cells present endogenous or cross-presented exogenous antigens on MHC class I molecules to naive CD8+ T-cells. Similar to CD4+ T-cell priming, co-stimulatory molecules (CD80/CD86) on DCs provide the necessary second signal for CD8+ T-cell activation. DCs release cytokines like IL-12, which promote the differentiation of CD8+ T-cells into cytotoxic T lymphocytes (CTLs).
Dendritic cells can acquire exogenous antigens and present them via MHC I molecules, allowing the activation of CD8+ T-cells even for pathogens that do not directly infect DCs. This is particularly important for the immune response to viruses, tumors, or intracellular bacteria.
Upon activation by dendritic cells, both CD4+ and CD8+ T-cells undergo clonal expansion, increasing their number to mount an effective immune response. CD4+ T-cells differentiate into distinct helper T-cell subsets, while CD8+ T-cells differentiate into cytotoxic T lymphocytes (CTLs), ready to target and kill infected or tumor cells.
Differentiated CD4+ T-cells coordinate the immune response by secreting cytokines, activating B-cells, macrophages, and CD8+ T-cells, and aiding in humoral and cell-mediated immunity.
Differentiated CD8+ T-cells (CTLs) recognize and kill infected cells or tumor cells through the release of cytotoxic molecules (e.g., perforin, granzymes).
Conclusion: Dendritic cells are crucial for the priming of both CD4+ and CD8+ T-cell responses. They capture, process, and present antigens on MHC molecules and provide essential co-stimulatory signals to activate naive T-cells. By also secreting cytokines, dendritic cells direct the differentiation of T-cells into appropriate subsets, which are essential for effective immune responses against pathogens and tumors. The ability of dendritic cells to cross-present antigens is particularly vital for generating strong CD8+ T-cell responses to non-infectious or extracellular pathogens.
Describe the order of events in naïve T cell activation.
Naïve T-cell activation is a crucial step in initiating adaptive immunity. It involves a series of tightly regulated events that ensure T-cells respond appropriately to pathogens while avoiding autoimmunity. The process can be broken down into distinct stages.
Naïve T-cells circulate through secondary lymphoid organs (e.g., lymph nodes), where they encounter dendritic cells (DCs) presenting antigens on their surface. The T-cell receptor (TCR) on the naïve T-cell recognizes and binds to a specific peptide-MHC complex (MHC class I for CD8+ T-cells, MHC class II for CD4+ T-cells) presented by the dendritic cell.
The TCR on the naïve T-cell binds to the peptide-MHC complex on the antigen-presenting cell (APC). This forms the primary signal (Signal 1) necessary for T-cell activation. For CD4+ T-cells, CD4 binds to the MHC class II molecule, and for CD8+ T-cells, CD8 binds to MHC class I, enhancing the specificity and affinity of the TCR-MHC interaction.
For full activation, the naïve T-cell also requires a second signal (Signal 2), which is provided by co-stimulatory molecules on the APC. The most important co-stimulatory molecules are CD80 and CD86 on the dendritic cell, which bind to CD28 on the T-cell. This interaction prevents T-cell anergy (unresponsiveness) and ensures that the T-cell is activated only in the presence of pathogen-derived antigens.
Dendritic cells release cytokines such as IL-12, IL-6, or type I interferons, depending on the pathogen encountered. These cytokines provide Signal 3, guiding the differentiation of the naïve T-cell into a specific effector subset (e.g., Th1, Th2, Th17, or regulatory T-cells for CD4+ T-cells, or cytotoxic T lymphocytes for CD8+ T-cells). The cytokines influence the differentiation pathway by promoting the expression of transcription factors that direct T-cell fate.
Once the T-cell receives all three signals, it becomes activated, leading to clonal expansion. The naïve T-cell rapidly proliferates to produce a population of identical T-cells, each recognizing the same antigen.
Activated T-cells start expressing effector molecules, such as cytokines (in the case of CD4+ T-cells) or cytotoxic molecules (in the case of CD8+ T-cells), preparing to perform their immune functions.
The cytokine environment and transcription factors dictate whether CD4+ T-cells differentiate into Th1, Th2, Th17, or Treg cells, each with distinct roles in immunity (e.g., Th1 promotes cell-mediated immunity, Th2 supports humoral immunity, Th17 mediates inflammation, Tregs suppress immune responses).
CD8+ T-cells differentiate into cytotoxic T lymphocytes (CTLs), which specialize in recognizing and killing infected or abnormal cells.
Following differentiation, T-cells upregulate chemokine receptors specific to the inflamed tissue, allowing them to migrate to sites of infection or injury. At the site of infection, CD4+ T-cells help other immune cells by releasing cytokines (e.g., IL-2 for T-cell proliferation, IFN-γ for macrophage activation). CD8+ T-cells directly kill infected or tumor cells by releasing cytotoxic molecules such as perforin and granzymes.
Once the pathogen is cleared, the majority of effector T-cells undergo apoptosis, a process regulated by immune checkpoint molecules and anti-apoptotic signals.
A small fraction of activated T-cells differentiate into memory T-cells, which persist long-term and provide rapid protection if the same pathogen is encountered in the future.
Conclusion: Naïve T-cell activation involves a series of highly coordinated steps, beginning with antigen recognition through the TCR, followed by co-stimulatory signaling, and the influence of cytokines. These signals drive T-cell activation, clonal expansion, and differentiation into specific effector subsets that perform distinct roles in immunity. The process ensures the immune system responds effectively to pathogens while establishing immunological memory for future encounters.
Describe the sequence of cellular events that occur during the activation of B-cells to secrete antibody.
The activation of B-cells to secrete antibodies is a multi-step process that begins with antigen recognition and ends with the production of antibodies. The sequence of cellular events can be summarized as follows:
Naive B-cells express B-cell receptors (BCRs), which are membrane-bound immunoglobulin molecules (IgM/IgD). These receptors are specific to a particular antigen. The B-cell encounters and binds to its cognate antigen (such as a pathogen or foreign molecule) through its BCR. This results in antigen internalization via receptor-mediated endocytosis.
After antigen binding, the antigen is internalized into endosomes and processed into small peptide fragments.
The processed peptides are loaded onto major histocompatibility complex class II (MHC II) molecules within the B-cell, which then presents these peptides on its surface for recognition by helper T-cells.
Activated CD4+ T-helper (Th) cells, particularly Th2 cells, recognize the antigen-MHC II complex on the B-cell surface through their TCR (T-cell receptor).
The interaction between the B-cell and the Th cell is reinforced by co-stimulatory signals. CD40 on the B-cell interacts with CD40L (CD154) on the Th cell, providing the necessary secondary signal (Signal 2) for B-cell activation.
The activated Th2 cells also secrete cytokines (e.g., IL-4, IL-5, IL-21) that stimulate B-cell proliferation, differentiation, and class-switch recombination.
The antigen recognition, T-cell help, and cytokine signals together activate the B-cell, leading to clonal expansion. The activated B-cell undergoes mitotic division, producing a population of B-cells that all recognize the same antigen.
B-cells rapidly proliferate in response to both antigenic stimulation and cytokine signaling from Th cells.
The cytokines released by Th2 cells (e.g., IL-4) induce the process of class-switch recombination (CSR) in the B-cell. This process changes the constant region of the antibody heavy chain, allowing the B-cell to produce different antibody isotypes (IgM to IgG, IgA, or IgE) depending on the nature of the immune response.
The specific cytokine environment determines the isotype of antibody the B-cell will secrete, which is important for the appropriate immune response (e.g., IgG for systemic defense, IgE for allergic responses).
A subset of activated B-cells differentiate into plasma cells, which are specialized for high-level antibody secretion. This process is driven by signaling through CD40 and the cytokine milieu. Plasma cells begin to synthesize and secrete large amounts of antibodies specific to the antigen. These antibodies are secreted into the bloodstream to neutralize the pathogen, opsonize it for phagocytosis, or activate the complement system.
A fraction of activated B-cells differentiate into memory B-cells, which persist long-term in the body. These memory B-cells retain the ability to respond more rapidly and robustly if the same antigen is encountered in the future.
Memory B-cells ensure faster and more effective secondary immune responses, producing antibodies more quickly upon re-exposure to the antigen.
Conclusion: B-cell activation to secrete antibodies involves several key steps: antigen recognition through the BCR, antigen processing and presentation on MHC II, T-cell help via CD40-CD40L interactions, and cytokine-driven signals that promote proliferation, class switching, and plasma cell differentiation. The final outcome is the secretion of antibodies that neutralize pathogens, along with the formation of memory B-cells that provide long-term immunity. This process ensures a highly specific and adaptive immune response to pathogens.
Explain the role of dendritic cells during the activation and clonal expansion of CD4+ and CD8+ T-cell responses to antigens.
Dendritic cells (DCs) are essential for initiating the adaptive immune response by activating both CD4+ and CD8+ T-cells. They are professional antigen-presenting cells (APCs) that play a central role in the activation, clonal expansion, and differentiation of these T-cells. Below is a detailed explanation of their role in the activation and clonal expansion of CD4+ and CD8+ T-cell responses to antigens.
Dendritic cells encounter pathogens or foreign antigens in peripheral tissues (e.g., skin, mucosal surfaces) via phagocytosis, endocytosis, or macropinocytosis. They internalize the antigen and transport it to secondary lymphoid organs (e.g., lymph nodes) for processing and presentation.
Once inside the DC, the antigen is degraded into smaller peptide fragments. These peptides are then loaded onto either MHC class I (for CD8+ T-cells) or MHC class II (for CD4+ T-cells) molecules for presentation.
Upon pathogen recognition or encountering inflammatory signals, DCs undergo maturation. They upregulate the expression of MHC molecules, co-stimulatory molecules (e.g., CD80, CD86), and cytokines, which are necessary for T-cell activation. After maturation, dendritic cells migrate from peripheral tissues to lymph nodes via the lymphatic system, where they encounter naïve T-cells.
In the lymph nodes, mature dendritic cells present processed antigen peptides on MHC class II molecules to naïve CD4+ T-cells. This interaction between the T-cell receptor (TCR) on the CD4+ T-cell and the MHC II-antigen complex provides the first signal for T-cell activation (Signal 1).
In addition to the TCR-MHC II interaction, dendritic cells provide essential co-stimulatory signals through the binding of CD80/CD86 on the DC to CD28 on the T-cell (Signal 2). This ensures proper T-cell activation and prevents anergy (lack of response).
Dendritic cells secrete cytokines (e.g., IL-12) that influence the differentiation of CD4+ T-cells into specific subsets (e.g., Th1, Th2, Th17, Treg). These subsets play distinct roles in immunity, such as promoting cell-mediated immunity (Th1), humoral immunity (Th2), or regulating immune responses (Treg).
Dendritic cells also present processed antigens on MHC class I molecules to CD8+ T-cells. This is crucial for activating cytotoxic T lymphocytes (CTLs), which are responsible for killing infected or tumor cells.
As with CD4+ T-cells, CD8+ T-cells require co-stimulatory signals (e.g., CD28-CD80/86) for full activation. Dendritic cells are essential for providing these signals to naïve CD8+ T-cells.
In certain cases, dendritic cells can cross-present exogenous antigens on MHC I molecules, allowing CD8+ T-cells to recognize and respond to pathogens that do not directly infect dendritic cells.
Once activated, both CD4+ and CD8+ T-cells undergo clonal expansion, where they proliferate to generate a large population of T-cells with identical TCRs specific to the antigen.
During clonal expansion, T-cells differentiate into effector cells. CD4+ T-cells differentiate into helper T-cell subsets (e.g., Th1, Th2, Th17) that produce cytokines and coordinate other aspects of the immune response. CD8+ T-cells differentiate into cytotoxic T lymphocytes (CTLs) that can kill infected or tumor cells.
After the immune response is resolved, a fraction of the activated T-cells differentiate into memory T-cells. These cells persist long-term and are capable of rapidly responding to subsequent infections by the same pathogen, leading to a more robust and faster immune response upon re-exposure.
Conclusion: Dendritic cells are critical for initiating and shaping both CD4+ and CD8+ T-cell responses. They capture, process, and present antigens via MHC molecules, and provide co-stimulatory signals that are necessary for full T-cell activation. Through the secretion of cytokines and the migration to lymphoid organs, dendritic cells ensure the differentiation of T-cells into appropriate effector subsets. Additionally, dendritic cells play a key role in generating memory T-cells, which provide long-term immunity. Their ability to activate and prime T-cells is central to the effectiveness of adaptive immune responses.
What is the purpose of peripheral tolerance? Explain the mechanisms of peripheral B-cell and T-cell tolerance.
Peripheral tolerance is a crucial immune regulatory mechanism that prevents the activation of self-reactive lymphocytes (B-cells and T-cells) that escape central tolerance. It ensures the immune system does not attack the body’s own tissues, thus preventing autoimmune diseases. This tolerance operates in the peripheral tissues (outside primary lymphoid organs like the thymus and bone marrow), where self-reactive immune cells can be regulated through various mechanisms to maintain immune homeostasis.
Anergy is a state of functional unresponsiveness in T-cells.
When a T-cell recognizes self-antigen presented by an antigen-presenting cell (APC) but does not receive the necessary co-stimulatory signals (e.g., CD28-CD80/86 interaction), it becomes anergic. This prevents the T-cell from becoming activated upon future antigen encounters, effectively silencing the self-reactive T-cell.
Tregs are a subset of CD4+ T-cells that actively suppress immune responses and maintain tolerance.
Tregs express the transcription factor Foxp3 and suppress self-reactive T-cells via cytokine secretion (e.g., IL-10, TGF-β) or direct cell-to-cell interactions, preventing autoimmunity.
Self-reactive T-cells can be eliminated in peripheral tissues. T-cells that recognize self-antigens without adequate co-stimulatory signals undergo activation-induced cell death (AICD), where repeated antigen exposure triggers apoptosis, effectively deleting autoreactive T-cells.
Certain tissues (e.g., the eye, brain) are immune-privileged, meaning they are less susceptible to immune responses. These tissues lack the usual co-stimulatory signals and are protected by immunosuppressive factors, allowing self-reactive T-cells to persist without initiating autoimmunity.
Anergy in B-cells occurs when self-reactive B-cells are unable to respond to antigens.
If a B-cell binds to self-antigen without receiving T-cell help (via CD40-CD40L interaction), it becomes anergic and cannot proliferate or produce antibodies, preventing autoimmunity.
Clonal deletion refers to the elimination of self-reactive B-cells in peripheral tissues. When a mature B-cell encounters a self-antigen without the necessary T-cell assistance, it may undergo apoptosis, thus removing the potential source of autoantibodies.
Regulatory B-cells (Bregs) play a role in maintaining immune tolerance. Bregs produce anti-inflammatory cytokines (e.g., IL-10, TGF-β) that suppress both B-cell and T-cell responses, thus controlling self-reactive immune cells and preventing autoimmune pathology.
Immune exclusion limits B-cell access to self-antigens in certain tissues. Specialized immune barriers in tissues like the eye or brain prevent the entry of autoreactive B-cells or restrict their ability to produce antibodies, minimizing the risk of autoimmune responses in these sensitive areas.
Conclusion: Peripheral tolerance mechanisms are essential for preventing autoimmune diseases by controlling self-reactive B-cells and T-cells that escape the central tolerance processes in primary lymphoid organs. These mechanisms include anergy, clonal deletion, the activity of regulatory cells (Tregs and Bregs), and immune exclusion in certain tissues. By ensuring that autoreactive lymphocytes are either suppressed, deleted, or rendered unresponsive, peripheral tolerance plays a critical role in maintaining immune homeostasis and preventing the development of autoimmunity.
Describe the role of the thymus in the development of T-cell central tolerance.
The thymus plays a pivotal role in the development of T-cell central tolerance, ensuring that T-cells capable of attacking the body’s own tissues are eliminated or regulated during their maturation. This process occurs through positive selection, negative selection, and the differentiation of regulatory T-cells (Tregs), ensuring self-tolerance and preventing autoimmunity.
Positive selection Ensures T-cells can recognize self-MHC molecules.
Developing T-cells (thymocytes) in the thymic cortex interact with cortical thymic epithelial cells (cTECs) presenting self-MHC molecules. Thymocytes that weakly or moderately bind self-MHC are allowed to survive, ensuring that the mature T-cells can effectively recognize antigen-MHC complexes on other cells. Thymocytes that fail to interact with MHC molecules undergo apoptosis.
Negative selection: Eliminates T-cells that strongly recognize self-antigens, preventing autoimmunity.
After positive selection, thymocytes move to the thymic medulla, where they encounter medullary thymic epithelial cells (mTECs) and dendritic cells presenting a diverse range of self-antigens. If a thymocyte’s TCR binds strongly to a self-antigen, it undergoes clonal deletion (apoptosis). This ensures that self-reactive T-cells are eliminated. Some self-reactive T-cells may also undergo anergy (functional inactivation) or differentiate into regulatory T-cells (Tregs), which help suppress immune responses in peripheral tissues.
Some self-reactive T-cells are converted into Tregs to maintain tolerance.
Thymocytes that recognize self-antigens with moderate affinity, but not strongly enough to undergo deletion, can be induced to differentiate into Foxp3+ Tregs. These Tregs play a crucial role in maintaining immune homeostasis by suppressing other self-reactive T-cells in peripheral tissues.
Thymic stromal cells (cTECs, mTECs, and dendritic cells) present self-peptides to developing T-cells, ensuring proper selection. AIRE (autoimmune regulator) in mTECs promotes the expression of a broad array of tissue-specific self-antigens, aiding the elimination of T-cells that could react against these tissues
The thymus provides a specialized microenvironment where positive and negative selection occur. The architecture and cellular interactions within the thymus ensure that only T-cells with appropriate reactivity to self-MHC and non-reactivity to self-antigens are allowed to mature and leave the thymus.
Conclusion: The thymus is critical for establishing T-cell central tolerance. Through positive and negative selection, it ensures that self-reactive T-cells are either deleted or regulated, preventing autoimmunity. The development of regulatory T-cells further reinforces tolerance, maintaining self-tolerance and immune homeostasis throughout the body.
Describe the process of B-cell V(D)J rearrangement [20 marks]
and comment on why this process is essential for adaptive immunity [5 marks].
a) B-cell V(D)J rearrangement is the process by which the variable region of the immunoglobulin (Ig) genes is assembled to generate a diverse repertoire of antibodies. This diversity is essential for the immune system to recognize a wide range of pathogens. The rearrangement process occurs in the bone marrow during B-cell development and involves the heavy chain and light chain genes.
The heavy chain of immunoglobulins is encoded by three gene segments: V (variable), D (diversity), and J (joining) segments.
D-J Rearrangement: In the first step, a D segment is joined to a J segment by a recombinase complex that includes the RAG1 and RAG2 enzymes. This forms the D-J exon.
V-DJ Rearrangement: Next, a V segment is randomly chosen and joined to the existing D-J exon, completing the variable region of the heavy chain.
Transcription and Translation: The rearranged V-DJ segment is transcribed into a primary RNA transcript, which is processed into the mature mRNA that will be translated into the immunoglobulin heavy chain protein.
The recombination is imprecise, allowing for additional diversity at the junctions of the V, D, and J segments, increasing the variability of the antibody repertoire.
The light chain of immunoglobulins is encoded by two gene segments: V (variable) and J (joining) segments.
A V segment is randomly chosen and recombined with a J segment, similar to the process in the heavy chain.
The recombined V-J segment is transcribed into RNA, which is then translated into a light chain protein.
There are two types of light chains, kappa (κ) and lambda (λ), and each B-cell only expresses one type. Only one allele of the light chain genes will undergo rearrangement, and if the rearrangement is unsuccessful, the second allele may attempt rearrangement.
During V(D)J recombination, the TdT (Terminal deoxynucleotidyl transferase) enzyme adds nucleotides to the junctions between the V, D, and J segments, increasing the diversity of the antibodies produced. This process is random and contributes significantly to the overall diversity.
Although not part of the initial V(D)J recombination, class switching occurs later in B-cell activation, allowing a single B-cell to produce different classes of antibodies (IgM, IgG, IgA, IgE) without altering the antigen specificity. Class switching involves recombination of the constant region of the antibody gene and is directed by cytokines in response to infection.
b) The primary purpose of V(D)J rearrangement is to generate a vastly diverse repertoire of antibodies, each with a unique antigen-binding site. This diversity enables the immune system to recognize and respond to an almost limitless variety of pathogens, such as bacteria, viruses, and fungi.
The process of V(D)J recombination allows the immune system to adapt to new pathogens by creating antibodies with high specificity to novel antigens. This is crucial for the effectiveness of the adaptive immune response, as it provides immunity against previously unencountered pathogens.
Once a B-cell successfully rearranges its immunoglobulin genes and encounters its specific antigen, it undergoes clonal expansion and produces large quantities of antibodies that target the pathogen. This is fundamental for a strong and effective immune defense.
Conclusion: V(D)J rearrangement is an essential process for the development of a diverse and adaptable B-cell repertoire. It ensures that the immune system can generate a wide array of antibodies capable of recognizing and combating diverse pathogens. The ability to adapt and respond to a vast range of antigens is a cornerstone of adaptive immunity, enabling the body to mount targeted responses to infections and protect against future encounters with similar pathogens.
Briefly describe the process involved in somatic hypermutation (SHM) and class switch recombination (CSR) and the purpose of the alterations that occur as a result of these processes.
Somatic hypermutation (SHM) occurs in activated B-cells after they encounter an antigen. It introduces point mutations in the variable region of the immunoglobulin (Ig) genes, leading to the generation of antibody diversity. SHM is critical for improving the affinity of antibodies during an immune response.
Activation-Induced Cytidine Deaminase is the key enzyme that initiates SHM. It deaminates cytosines in the variable (V) region of the antibody gene, converting them to uracils.
The uracils are recognized and processed by repair enzymes, which result in mutations (insertions, deletions, or base substitutions) in the DNA sequence.
This leads to point mutations in the antigen-binding site, potentially altering the affinity of the antibody for the antigen.
B-cells with higher-affinity antibodies for the antigen are selected through affinity maturation. These cells receive survival signals and undergo clonal expansion.
B-cells with low-affinity or self-reactive antibodies are eliminated through apoptosis.
The primary purpose of SHM is to increase antibody affinity for the antigen over the course of an immune response, a process called affinity maturation. This enhances the effectiveness of the immune response, ensuring the production of high-affinity antibodies capable of neutralizing pathogens more efficiently.
Class switch recombination (CSR) is a process that allows a B-cell to switch the class of antibody it produces without changing its specificity for the antigen. This enables a more tailored immune response by producing antibodies with different effector functions (e.g., IgM, IgG, IgA, IgE).
Activation-Induced Cytidine Deaminase is also involved in CSR. It induces double-strand breaks in the constant (C) region genes of the immunoglobulin heavy chain locus, leading to recombination between different constant region genes (e.g., switching from IgM to IgG or IgA).
The breaks in the DNA are repaired, leading to the recombination of the variable region with a different constant region gene. This results in a new isotype of antibody while retaining the same antigen specificity.
The type of class switch is influenced by cytokines released by helper T-cells (e.g., IL-4, IFN-γ, TGF-β). Each cytokine promotes the switching to a specific antibody class (e.g., IL-4 induces IgE, IFN-γ induces IgG).
The purpose of CSR is to adapt the immune response by producing antibodies with different effector functions. For example, switching from IgM (first responder) to IgG provides longer-lasting immunity, while switching to IgA is important for mucosal immunity. IgE is important for defending against parasitic infections and in allergic responses.
CSR allows the immune system to tailor the antibody response based on the nature of the pathogen and the location of infection.
Conclusion: Somatic hypermutation (SHM) and class switch recombination (CSR) are essential processes for refining and adapting the immune response. SHM improves the affinity of antibodies for specific antigens, while CSR allows the production of different antibody isotypes with diverse effector functions. Together, these processes enhance the specificity, efficacy, and adaptability of the immune system in combating infections.
