Physiology of Immunity

Introduction

• Immunity integrates innate defenses such as natural killer cells and phagocytes with adaptive responses mediated by T and B lymphocytes.
• Cellular and humoral mechanisms target diverse pathogens, while helper cells and complement coordinate responses, and therapeutic antibodies enhance immune modulation.

• Immunity refers to the body’s defense against harmful agents that threaten normal health.
• The environment contains numerous pathogens, including bacteria, viruses, fungi, and parasites.
• When these organisms enter the body, they can multiply and cause disease if not controlled.
• Effective protection requires rapid and continuous defense mechanisms to eliminate pathogens.
• The strength of protection depends on the efficiency of the immune system.
• Defense mechanisms are broadly classified into non specific and specific responses.
• Non specific defenses provide immediate protection, while specific responses are targeted and adaptive.
• Immune responses vary depending on the type of pathogen and the site of infection.
• These coordinated mechanisms help maintain health and prevent disease progression.

Classification Of Immunity

• Immunity is the ability of the body to recognize and eliminate foreign substances or pathogens.
• The immune response involves recognition of the antigen followed by an effective response to remove it.
• Immunity is broadly classified into innate immunity and acquired immunity.

Innate immunity:

• Innate immunity provides immediate, non specific defense against pathogens.
• It includes mechanisms such as phagocytosis, inflammation, cytokine release, and activation of the complement system.
• This type of immunity is present from birth and operates without prior exposure.

Acquired immunity:

• Acquired immunity is specific and develops after exposure to particular antigens.
• It involves activation of lymphocytes that recognize and eliminate specific pathogens.
• This response is more precise and may generate immunological memory for future protection.
• Both systems work together to provide effective host defense.

Nonspecific Defense System (Innate Immunity)

• Innate immunity provides immediate, non specific protection against pathogens.
• It includes mechanical barriers such as skin and mucous membranes that prevent entry.
• Chemical defenses involve antimicrobial substances like interferons and complement proteins.
• Natural killer cells destroy infected or abnormal cells.
• Phagocytic cells engulf and eliminate pathogens.
• Inflammation and fever enhance immune response and limit infection spread.

Mechanical Defense

Skin and epidermis:

• Mechanical defenses form the first line of protection by preventing entry of pathogens into the body.
• The skin acts as a strong physical barrier separating internal tissues from the external environment.
• Damage to skin, such as burns, increases risk of infection and septicemia.

Mucous membranes:

• Mucous membranes line body cavities and trap microorganisms through surface secretions.
• They also produce substances that inhibit microbial growth.

Mucus:

• Mucus secreted by epithelial glands traps microbes in respiratory, gastrointestinal, and genitourinary tracts.
• Trapped particles are prevented from reaching deeper tissues.

Hairs:

• Hair present at body openings filters dust and microorganisms, reducing entry of pathogens.

Cilia:

• Cilia in respiratory epithelium move mucus along with trapped particles toward the exterior.
• This coordinated action forms the mucociliary clearance mechanism.

Tear:

• Tears from lacrimal glands wash away microbes and dilute harmful substances.
• They also contain antimicrobial components.

Saliva:

• Saliva cleanses the oral cavity and reduces microbial load.
• It contains enzymes and antimicrobial factors that inhibit bacterial growth.

Urine:

• Urine flow flushes microorganisms from the urinary tract, preventing colonization.

Defecation:

• Defecation removes microorganisms from the lower gastrointestinal tract along with fecal matter.
• These mechanical processes work continuously to provide immediate, non specific protection against infection.

Table 19.1: Types of immunity.

Immunity Type	Subtype	Mechanism and Examples
Innate immunity	Non specific, natural killer cell mediated	Immediate defense without prior exposure; no memory
Acquired immunity	Natural active	Infection induces cellular and humoral responses with memory
	Natural passive	Maternal antibodies (Immunoglobulin G via placenta, Immunoglobulin A via breast milk)
	Artificial active	Vaccination induces protective immune memory
	Artificial passive	Antibody administration, for example anti D therapy

Chemical Defense

• Chemical defenses are part of innate immunity that inhibit growth and survival of microorganisms.
• The acidic pH of skin restricts microbial proliferation.
• Sebum contains unsaturated fatty acids with bactericidal action.
• Secretions such as saliva, tears, and sweat contain lysozyme, which destroys bacterial cell walls.
• The acidic gastric environment eliminates many ingested microbes and inactivates toxins.
• Low vaginal pH provides protection against pathogen entry.
• Complement proteins in plasma enhance microbial destruction by opsonization and promoting phagocytosis.
• They also contribute to inflammatory responses.
• Interferons are antiviral proteins that inhibit viral replication and protect neighboring cells.

Defense by NK Cells

NK Cells

• Natural killer cells are a distinct group of lymphocytes that are neither B cells nor T cells.
• They function in innate immunity and rapidly destroy infected or malignant cells.
• They do not undergo maturation in the thymus and lack antigen specific receptors.
• These cells express surface markers such as CD16 and CD56, but not CD3.
• They are large granular lymphocytes and constitute about 10 to 15 percent of circulating lymphocytes.
• They are present in blood, spleen, lymph nodes, and bone marrow.
• Natural killer cells recognize and destroy virus infected cells and tumor cells.
• They also identify antibody coated targets and mediate antibody dependent cellular cytotoxicity.

Mechanism of Killing

• The mechanism of killing involves release of perforins, which create pores in target cell membranes, causing lysis.
• They also release cytokines, including interferons, which enhance phagocytic activity and immune responses.
• Fc receptors enable binding to antibody coated cells, facilitating targeted destruction.
• These cells act without prior sensitization and do not require major histocompatibility complex recognition.
• They serve as an early defense against viral infections and malignancy.
• Natural killer cells preferentially attack cells with reduced or abnormal surface markers, ensuring rapid immune surveillance.

Defense by Phagocytic Cells

Role of Granulocytes and Mononuclear Cells

• Phagocytic cells provide an important defense by ingesting and destroying microorganisms.
• Major phagocytes include neutrophils, monocytes, and macrophages.
• Monocytes circulate in blood and differentiate into macrophages in tissues.
• Phagocytosis involves uptake of microbes or foreign particles followed by intracellular destruction.
• The process includes chemotaxis, adherence, ingestion, and intracellular killing.
• Macrophages are classified as wandering or fixed cells based on mobility.
• Wandering macrophages migrate through tissues, while fixed macrophages remain in specific sites.
• The collection of these cells forms the mononuclear phagocyte system, widely distributed in the body.
• Examples include Kupffer cells in liver, alveolar macrophages in lungs, microglial cells in brain, and macrophages in spleen and lymph nodes.
• Additional members include osteoclasts in bone and Langerhans cells in skin.
• Granulocytes, especially neutrophils, provide rapid response to infection.
• These cells work together to eliminate pathogens and maintain tissue homeostasis.

Defense by Inflammation and Fever

• Inflammation eliminates microorganisms through chemical mediators released by immune cells and by phagocytosis.
• Fever enhances immune activity and inhibits microbial growth, aiding host defense.

Inflammation

• Inflammation is a protective tissue response to injury or infection that aims to eliminate harmful agents and promote healing.
• It is characterized by redness, heat, swelling, pain, and loss of function at the affected site.
• These changes result from increased blood flow and release of inflammatory mediators.
• Inflammation helps destroy microorganisms, neutralize toxins, and initiate tissue repair, restoring normal function.

Stages of Inflammation

• The process occurs in three main stages: vascular changes, cellular response, and repair.

Vasodilation and Increased Permeability

• In the initial stage, vasodilation increases blood flow, producing redness and warmth.
• This is followed by increased vascular permeability, allowing plasma proteins and immune cells to enter tissues.
• Fluid accumulation leads to swelling and contributes to pain.
• Chemical mediators such as histamine, prostaglandins, bradykinin, and complement proteins regulate these vascular changes.
• Endothelial cell contraction increases intercellular gaps, enhancing permeability.
• In the second stage, phagocytic cells migrate to the site through chemotaxis.
• These cells ingest and destroy pathogens and debris by phagocytosis.
• In the final stage, tissue repair occurs through regeneration or fibrosis, depending on the extent of damage.
• The inflammatory response also produces the triple response, including localized redness, surrounding flare, and swelling.
• Overall, inflammation is essential for host defense and maintenance of tissue integrity.

Phagocyte Migration and Phagocytosis

• During inflammation, phagocytes rapidly accumulate at the site of injury.
• Neutrophils arrive first, followed by monocytes that differentiate into macrophages.
• These cells migrate through blood vessel walls by diapedesis and move toward signals by chemotaxis.
• They ingest and destroy microorganisms through phagocytosis.
• Many phagocytes die after microbial killing, along with damaged tissue cells.
• This leads to formation of pus, a viscous collection of dead cells and debris.
• Pus may be gradually absorbed, but if localized, it forms an abscess.

Tissue Repair

• Tissue repair represents the final phase of inflammation and restores structural integrity.
• Fibroblasts, macrophages, and epithelial cells migrate to the injured site and release growth factors.
• These factors promote regeneration of epithelium and healing of damaged tissue.
• Keratinocyte migration is enhanced by tissue plasmin, aiding surface repair.
• Deposition of collagen fibers leads to formation of scar tissue when regeneration is incomplete.

Role of NF-kB

• Nuclear factor kappa B is an important regulator of inflammation at the molecular level.
• It remains inactive in cytoplasm when bound to inhibitory proteins.
• Inflammatory stimuli activate it, allowing movement into the nucleus.
• It promotes transcription of genes encoding inflammatory mediators.
• Thus, this factor plays a key role in coordinating inflammatory and repair processes.

Systemic Response to Inflammation

• Systemic response to inflammation is mediated by cytokines released from activated immune cells.
• These cytokines stimulate the liver to produce acute phase proteins.
• Acute phase proteins are plasma proteins that increase significantly during inflammation.
• Important examples include C reactive protein, fibrinogen, haptoglobin, and complement proteins.
• C reactive protein rises rapidly in early inflammation and serves as a sensitive clinical marker.
• Its levels decline quickly as inflammation resolves.
• Fibrinogen increases more slowly and remains elevated for a longer duration.
• Elevated fibrinogen contributes to increased erythrocyte sedimentation rate.
• Increased erythrocyte sedimentation rate occurs due to reduced repulsion between red cells.
• Measurement of these markers helps assess severity and progression of inflammatory disorders.

Inflammatory Cells and Cytokines

• Acute inflammation mainly involves neutrophils, eosinophils, and basophils.
• Chronic inflammation involves monocytes, macrophages, lymphocytes, and plasma cells.
• These cells eliminate pathogens by phagocytosis and by releasing cytokines, which regulate inflammatory responses.

Fever

• Fever is a protective response during infection and inflammation.
• Elevated body temperature inhibits growth and replication of many microorganisms.
• It enhances the activity of interferons and immune enzymes, improving host defense.
• Moderate fever supports immune function, but very high temperature requires control to prevent harmful effects.

Contribution of Toll-like Receptors

• Toll like receptors are important components of innate immunity that recognize microbial structures.
• They detect pathogen associated molecular patterns on bacteria, fungi, and viruses.
• Activation of these receptors triggers intracellular signaling pathways.
• This leads to transcription of genes involved in inflammatory and immune responses.
• Toll like receptor 4 recognizes bacterial components and initiates immune activation.
• Thus, these receptors play a key role in early host defense.

Pattern Recognition Receptors:

• Pattern recognition receptors detect conserved molecular patterns present on pathogens.
• Toll like receptors are major receptors that initiate innate immune responses.
• Some receptors, such as nucleotide binding oligomerization domain proteins, function inside cells.
• NOD2 is associated with inflammatory disorders, including inflammatory bowel disease, indicating its clinical importance.

Specific Defense Mechanisms (Acquired Immunity)

• Acquired immunity is a specific defense mechanism that develops after exposure to antigens.
• It is mediated by specialized lymphocytes and shows specificity and memory.
• It is classified into cell mediated immunity and humoral immunity.

Cellular Immunity:

• Cell mediated immunity is carried out by cytotoxic T lymphocytes.
• These cells recognize and destroy infected or abnormal cells.
• It is effective against intracellular pathogens, including viruses, certain parasites, fungi, and malignant cells.

Humoral Immunity:

• Humoral immunity is mediated by antibodies produced by plasma cells derived from B lymphocytes.
• Antibodies neutralize pathogens and toxins present in body fluids.
• It is mainly effective against extracellular microorganisms, especially bacteria.
• In most infections, both cellular and humoral responses are activated together.
• This coordinated response enhances overall immune protection.

Development of Immunity

• Development of immunity involves formation, maturation, and activation of lymphocytes in response to specific antigens.
• Each antigen induces proliferation of a specific lymphocyte clone, ensuring targeted immune response.
• Lymphocytes are classified into B lymphocytes, T lymphocytes, and natural killer cells.
• Natural killer cells mainly contribute to innate defense, while B and T lymphocytes mediate adaptive immunity.
• Lymphocyte development occurs in primary lymphoid organs, where precursor cells differentiate and mature.
• T lymphocytes mature in the thymus, while B lymphocytes mature in bone marrow and fetal liver.
• These sites provide the environment for acquisition of immunological competence.
• After maturation, lymphocytes enter circulation and migrate to secondary lymphoid organs.
• These include lymph nodes, spleen, and mucosa associated lymphoid tissues.
• In these organs, lymphocytes encounter antigens and undergo activation, proliferation, and differentiation.
• The coordinated interaction of primary and secondary lymphoid organs ensures efficient immune surveillance.
• This process enables the body to generate specific responses and immunological memory against pathogens.

Development of Bursa:

• In birds, the bursa of Fabricius is a primary lymphoid organ located near the cloaca.
• It is responsible for the development and maturation of B lymphocytes.
• Immature pre-B cells differentiate into functional B cells within this organ.
• Therefore, these lymphocytes are termed bursa-dependent cells.
• Mammals lack a bursa but possess functional equivalents.
• The bone marrow and fetal liver serve as sites for B cell development in mammals.

Development of Gut-Associated Lymphoid Organs:

• Gut-associated lymphoid tissue is distributed throughout the gastrointestinal tract, extending from the oral cavity to the colon.
• Tonsils in the oral cavity and pharynx contain lymphoid follicles that initiate immune responses.
• Aggregated lymphoid nodules, called Peyer’s patches, are present in the submucosa of the small intestine, especially the ileum.
• The vermiform appendix contains abundant lymphoid tissue and contributes to immune surveillance.
• Scattered lymphoid cells are also found in the colon.
• These structures protect against pathogens, parasites, and harmful antigens entering through the intestinal lumen.

Table 19.2: Distribution of T and B cells in various lymphatic tissues of the body.

Tissue	T lymphocytes (%)	B lymphocytes (%)
Thymus	100	0
Bone marrow	10	90
Spleen	45	55
Lymph node	60	40
Blood	80	20

Development of T Cells

Mechanism of Development

• T lymphocytes develop within the thymus, a primary lymphoid organ essential for cell-mediated immunity.
• Hematopoietic stem cells migrate from the bone marrow to the thymus as immature pre-T cells.
• Migration is guided by chemotactic signals released by thymic tissue rather than by random movement.
• Molecules associated with major histocompatibility complex class I may contribute to this directed migration.
• Early precursor cells are multipotent, but the thymic microenvironment commits them to the T cell lineage.
• Developing cells initially express surface markers such as CD7, indicating early T lineage differentiation.
• The thymus provides a specialized microenvironment composed of epithelial cells, macrophages, and dendritic cells.
• These supporting cells express major histocompatibility complex class II molecules, which are essential for T cell maturation.
• Thymic epithelial cells play a central role in differentiation, selection, and survival of developing T cells.
• Specialized epithelial cells, called thymic nurse cells, enclose immature thymocytes within cytoplasmic compartments.
• These cells secrete interleukin-7, which promotes proliferation and differentiation of developing T cells.
• Progressive maturation involves selection processes that ensure functional and self-tolerant T lymphocytes.

Steps of Development

• Precursor cells from bone marrow enter the thymus and localize in the subcapsular cortex.
• These cells enlarge into rapidly dividing lymphoblasts with self-renewal capacity.
• Lymphoblasts proliferate and differentiate into immature pre-T cells.
• Progressive maturation converts pre-T cells into functional T lymphocytes.
• Immature cells acquire antigen receptors and become naive T cells capable of antigen recognition.
• Further activation produces proliferating T immunoblasts.
• Two major subsets arise: CD8-positive cells, which become cytotoxic T cells, and CD4-positive cells, which become helper T cells.
• Maturing cells migrate from the cortex to the medulla for final selection.
• Mature T cells exit the thymus through postcapillary venules and lymphatic channels.
• These cells populate secondary lymphoid organs, including lymph nodes and spleen.
• Circulating T lymphocytes mediate cell-mediated immunity by targeting infected or abnormal cells.

Changes during Development

• During thymic maturation, developing T lymphocytes undergo structural and functional modifications.
• These changes enable recognition of specific antigens and effective immune responses.
• One major change is the formation of T cell receptors on the cell surface.
• These receptors are composed of polypeptide chains forming either alpha–beta or gamma–delta types.
• Approximately 95 percent of circulating T cells possess alpha–beta receptors, while about 5 percent express gamma–delta receptors.
• These receptors allow precise antigen recognition in association with major histocompatibility complex molecules.
• Another important change is the synthesis of cytokines that regulate immune activity.
• Key cytokines include interferons and lymphotoxin, which contribute to immune defense mechanisms.
• Mature T cells acquire the ability to destroy infected or abnormal cells.
• These developmental changes ensure functional competence and specificity of the adaptive immune response.

Types of T Cells

• T lymphocytes are broadly classified into helper, cytotoxic, and memory T cells based on their functions.

Helper T Cells (T₄ Cells)

• Helper T cells express the CD4 receptor on their surface.
• They regulate both cell-mediated and humoral immune responses.
• These cells activate B lymphocytes, macrophages, and other immune cells.
• Two functional subsets are recognized.
• Type 1 helper cells promote cellular immunity by activating macrophages and cytotoxic T cells.
• They secrete cytokines such as interleukin-2 and interferon.
• Type 2 helper cells enhance humoral immunity by stimulating antibody production.
• They release cytokines including interleukins 4, 5, 6, and 10.

Cytotoxic T Cells

• Cytotoxic T cells carry the CD8 receptor on their membrane.
• They directly destroy virus-infected, tumor, and transplanted cells.
• Cell death is induced through release of perforin and granzymes.
• These cells play a central role in eliminating intracellular pathogens.

Memory T Cells

• A small proportion differentiates into long-lived memory T cells.
• These cells persist in lymphoid tissues and circulation for many years.
• Upon re-exposure to the same antigen, they respond rapidly and vigorously.
• This rapid response provides long-lasting and specific immunological memory.

T Cell Receptor

• The T cell receptor is a membrane-bound complex responsible for antigen recognition.
• In about 95 percent of T cells, the receptor is composed of alpha and beta chains.
• A smaller proportion contains gamma and delta chains forming an alternative receptor type.
• Each chain has variable and constant regions, similar to immunoglobulins.
• The variable regions bind antigenic peptides presented with major histocompatibility complex molecules.
• The receptor is associated with the CD3 complex, which transmits activation signals into the cell.
• These structural features ensure specificity and activation of T lymphocytes during immune responses.

TCR Gene Arrangement

• The genetic organization of the T cell receptor resembles that of immunoglobulin genes.
• The beta chain gene is located on chromosome 7, while the alpha chain gene is on chromosome 14.
• All somatic cells carry these genes in an unrearranged form, but rearrangement occurs only in developing T lymphocytes.
• The beta chain gene contains variable, diversity, joining, and constant segments.
• During maturation, one segment from each region combines after removal of intervening DNA sequences.
• The rearranged gene is then transcribed into messenger ribonucleic acid for protein synthesis.
• Multiple segment combinations generate diverse antigen-binding specificities.
• Rearrangement of the beta chain occurs before that of the alpha chain.

T Cell Ontogeny

• Progenitor T cells originate in bone marrow and migrate to the thymus for maturation.
• Maturation involves gene rearrangement, expression of surface proteins, and development of self-tolerance.
• Early cortical thymocytes express markers such as CD7, terminal deoxynucleotidyl transferase, and cytoplasmic CD3.
• Cells destined to form alpha–beta receptors first rearrange the beta chain gene, followed by the alpha chain gene.
• Functional T cell receptors appear on the surface along with the CD3 complex.
• Initially, developing cells express both CD4 and CD8 markers.
• With maturation, each cell retains either CD4 or CD8, but not both.
• CD4-positive cells differentiate into helper T cells, while CD8-positive cells become cytotoxic T cells.
• Fully mature T lymphocytes leave the thymus and enter circulation.
• These cells populate peripheral lymphoid organs and participate in immune responses.

Development of B Cells

• B lymphocytes originate from hematopoietic stem cells and mature in primary lymphoid tissues.
• In mammals, development occurs in the bone marrow and fetal liver, which act as bursa equivalents.
• In birds, maturation takes place in a specialized organ near the cloaca that supports B cell differentiation.
• Early precursor cells differentiate into pre-B cells within these tissues.
• During maturation, B cells acquire surface antigen receptors and receptors for regulatory cytokines.
• A critical event is immunoglobulin gene rearrangement, which begins with the heavy chain and is followed by the light chain.
• This process generates a diverse repertoire of antigen-specific receptors.
• Immature B cells become naive B cells capable of recognizing specific antigens.
• Each B cell is committed to producing one unique antibody, ensuring specificity of response.
• After maturation, B cells migrate to peripheral sites such as lymph nodes, spleen, and lymphoid follicles.
• In these regions, they may transform into proliferating B immunoblasts upon antigen exposure.
• Activated cells differentiate into plasma cells, which synthesize large quantities of antibodies.
• Plasma cells are typically absent from circulating blood under normal conditions.
• Antibodies produced by plasma cells neutralize pathogens and facilitate their removal.
• Some activated B cells differentiate into long-lived memory B cells.
• These cells persist for years and respond rapidly to repeated exposure to the same antigen.
• Memory responses are faster and more effective than primary immune responses.
• The entire process ensures efficient humoral immunity and long-term immunological protection.

Antigens

Definition

• Antigens are substances that enter the body and trigger a specific immune response.
• They are usually proteins or polysaccharides derived from microorganisms, toxins, or foreign cells.
• Antigens possess two essential properties: immunogenicity and reactivity.
• Immunogenicity refers to the ability to stimulate production of antibodies or activation of T lymphocytes.
• Reactivity is the capacity to bind specifically with antibodies or immune cells.
• A complete antigen exhibits both immunogenicity and reactivity.
• A hapten shows reactivity but lacks immunogenicity unless attached to a carrier molecule.

Nature of Antigen

• Antigens may be whole microorganisms such as bacteria or viruses, or their structural components like cell walls, capsules, or flagella.
• They may also include nonmicrobial substances such as pollen, egg proteins, transplanted tissues, or incompatible blood cells.
• Chemically, antigens are typically large and complex molecules, most commonly proteins.
• Other antigenic substances include glycoproteins, nucleoproteins, and large polysaccharides.
• T lymphocytes mainly respond to protein antigens, whereas B lymphocytes can recognize both protein and non-protein antigens.

Antigenic Determinant

• The specific reactive region of an antigen is called the epitope.
• A single antigen usually contains multiple epitopes, each capable of inducing a specific immune response.

MHC Antigens

• Major histocompatibility complex molecules are self-antigens that enable recognition of foreign substances.
• They are also termed human leukocyte antigens and are present on most nucleated cells.
• Mature red blood cells lack these molecules but carry distinct blood group antigens.
• Chemically, these molecules are glycoproteins composed of alpha and beta chains.
• Two main classes are recognized: class one on all nucleated cells and class two on antigen-presenting cells.
• Their primary function is to bind and present antigenic peptides to T lymphocytes.
• This presentation is essential for initiating cell-mediated immunity.
• They also play a crucial role in tissue compatibility and transplant rejection.
• Effective immune activation depends on accurate antigen recognition by these molecules.

Types of MHC Antigens

• Major histocompatibility complex class one molecules are present on all nucleated cells, except mature red blood cells.
• They consist of one alpha chain associated with beta-2 microglobulin.
• These molecules present endogenous peptides to cytotoxic T lymphocytes.
• Major histocompatibility complex class two molecules are found on antigen-presenting cells such as macrophages and dendritic cells.
• They contain two alpha and two beta chains.
• These molecules present exogenous peptides to helper T lymphocytes.

Mechanism of Action of MHC Antigens

• Cellular proteins are continuously degraded into peptide fragments within cells.
• Major histocompatibility complex class one molecules bind peptides of about 8–10 amino acids derived from intracellular proteins.
• Major histocompatibility complex class two molecules present peptides of about 13–17 amino acids from extracellular sources.
• These peptide–molecule complexes are displayed on the cell surface for immune surveillance.
• When peptides originate from self proteins, T lymphocytes remain unresponsive, maintaining tolerance.
• When peptides are derived from foreign antigens, T lymphocytes become activated.
• Activated cells initiate cell-mediated immune responses to eliminate infected or abnormal cells.

Significance of HLA Antigens

• These molecules are essential for tissue compatibility during organ transplantation.
• They play a central role in antigen recognition and immune activation.
• They are involved in transfusion reactions, including platelet refractoriness and graft-versus-host disease.
• Certain variants are associated with increased susceptibility to specific diseases.
• Human leukocyte antigen typing is useful in transplantation matching and selected forensic applications.

Recognition of MHC-Ag Complex by TCR

• The T cell receptor recognizes antigenic peptides only when presented with major histocompatibility complex molecules on antigen-presenting cells.
• This combined structure is termed the major histocompatibility complex–antigen complex.
• Most T cells possess receptors formed by alpha and beta chains, which function as heterodimers.
• These receptors simultaneously bind the antigenic peptide and the major histocompatibility complex molecule.
• This dual recognition ensures specificity and appropriate immune activation.
• A smaller subset contains gamma and delta receptors, which are less dependent on classical antigen presentation.
• These cells are abundant in mucosal tissues, especially in the gastrointestinal tract.
• They contribute to early immune responses and secrete regulatory cytokines.

Cellular Immunity

• Cellular immunity is mediated primarily by T lymphocytes.
• It is especially effective against intracellular pathogens such as viruses, certain parasites, and fungi.
• It also targets tumor cells and transplanted tissues.
• Antigens must be processed by antigen-presenting cells before recognition.
• These cells present antigenic peptides with major histocompatibility complex molecules.
• This interaction activates T lymphocytes, leading to proliferation and targeted destruction of infected or abnormal cells.

Steps of Cellular Immunity

• Antigen-presenting cells recognize, process, and present antigens with major histocompatibility complex molecules.
• T lymphocytes become activated and proliferate.
• Activated cells eliminate infected or abnormal cells.

Antigen Recognition, Processing and Presentation

• The immune system can recognize a wide range of antigens through diverse lymphocyte receptors.
• This diversity arises during development, allowing each T lymphocyte or B lymphocyte to respond to a specific antigen.
• B lymphocytes can directly bind antigens through surface receptors and become activated.
• In contrast, T lymphocytes require antigen processing before activation.
• Antigen-presenting cells internalize antigens and degrade them into peptide fragments.
• These peptides are displayed on the cell surface with major histocompatibility complex molecules.
• Key antigen-presenting cells include macrophages, dendritic cells, and B lymphocytes.
• These cells are abundant in areas exposed to the external environment.
• Important locations include the skin and mucosal surfaces of respiratory, gastrointestinal, and genitourinary tracts.
• Presentation of antigenic peptides ensures precise recognition and activation of T lymphocytes.

Steps of Antigen Presentation

• Antigen presentation involves sequential events carried out by antigen-presenting cells.
• The first step is ingestion of antigen through endocytosis or phagocytosis.
• Internalized material is enclosed within vesicles inside the cytoplasm.
• The second step is digestion, where lysosomal enzymes degrade antigens into peptide fragments.
• These fragments are retained within vesicular structures.
• Simultaneously, major histocompatibility complex class two molecules are synthesized within the cell.
• The third step is fusion of vesicles, where antigen-containing vesicles merge with those carrying these molecules.
• This fusion allows interaction between peptides and major histocompatibility complex molecules.
• The fourth step is binding, in which peptide fragments attach to the binding groove of these molecules.
• This forms a stable antigen–major histocompatibility complex complex.
• The fifth step is membrane expression, where the complex is transported to the cell surface.
• The complex becomes embedded in the plasma membrane during exocytosis.
• These activated cells migrate to lymphoid tissues or circulate in blood.
• When they encounter specific T lymphocytes, the complex binds to the T cell receptor.
• This interaction activates T lymphocytes and initiates cell-mediated immune responses.

Immunologic Synapse

• The immunologic synapse is the specialized junction between a T lymphocyte and an antigen-presenting cell.
• It forms when the T cell receptor binds to the antigen–major histocompatibility complex on the presenting cell.
• Surrounding adhesion molecules stabilize this interaction and align signaling components.
• Effective activation requires two signals for proper immune response.
• The first signal is antigen recognition by the T cell receptor.
• The second signal is provided by co-stimulatory interactions between surface proteins.
• Absence of the second signal leads to functional inactivation of the T lymphocyte.
• This mechanism prevents inappropriate or excessive immune activation.

Activation and Proliferation of T Cells

• Cellular immunity depends on activation of T lymphocytes by specific antigens.
• Activated cells undergo rapid proliferation and differentiation.
• They form effector T cells that eliminate infected or abnormal cells.
• This process includes activation followed by expansion and maturation of T lymphocytes.

Activation of T Cells

• T lymphocytes possess surface T cell receptors that recognize antigenic peptides presented with major histocompatibility complex molecules on antigen-presenting cells.
• Binding of this complex provides the primary signal required for activation.
• Additional co-stimulatory signals are essential for full activation and prevention of anergy.

Proliferation and Differentiation of T Cells

• Activated T lymphocytes enter the cell cycle and undergo rapid clonal expansion.
• They differentiate into specialized effector and long-lived cells.
• One major subset is cytotoxic T cells, which express CD8 molecules.
• These cells destroy infected, malignant, or transplanted cells by releasing cytotoxic proteins.
• Another subset forms memory T cells, which persist for extended periods.
• Memory cells respond rapidly and efficiently upon re-exposure to the same antigen.
• This process ensures effective elimination of pathogens and development of long-term cellular immunity.

Elimination of the Invader

• Cytotoxic T cells eliminate infected or abnormal cells through multiple mechanisms.
• In cytolysis, they release perforin and granzymes that create membrane pores and induce apoptosis.
• They also secrete lymphotoxins, including tumor necrosis factor beta, which contribute to cell destruction.
• Interferon gamma is released to inhibit viral replication and enhance macrophage activity.
• These actions improve phagocytosis and antigen clearance.
• Cellular immunity is particularly effective against intracellular pathogens.
• It plays a key role in viral and certain fungal infections.
• It also targets tumor cells and transplanted tissues.
• Chronic bacterial and parasitic infections are controlled through this mechanism.

Humoral Immunity

• Humoral immunity is mediated by antibodies produced by plasma cells.
• Plasma cells arise from activated B lymphocytes following antigen exposure.
• Activation of B lymphocytes leads to their differentiation and proliferation.
• Many antigens can directly stimulate B lymphocytes without processing.
• However, antigen presentation can enhance B cell activation and response.
• Antibodies circulate in body fluids and neutralize pathogens effectively.

Steps of Humoral Immunity

• Antigen presentation initiates activation of B lymphocytes.
• Activated B lymphocytes undergo clonal expansion and differentiation.
• They form plasma cells, which secrete specific antibodies.
• Antibodies neutralize pathogens and activate the complement system.
• Some cells become memory B cells.
• Memory cells ensure rapid and enhanced responses upon re-exposure to the same antigen.

Presentation of Antigen

• In humoral immunity, B lymphocytes can act as antigen-presenting cells.
• Direct antigen binding to surface immunoglobulin receptors can initiate activation.
• Antigen presentation with major histocompatibility complex class two molecules can further enhance activation.

Activation of B Cells

• Some antigens activate B lymphocytes independently, while others require T cell assistance.
• Helper T lymphocytes provide essential co-stimulatory signals for full activation.
• These cells release cytokines such as interleukins that promote B cell growth and differentiation.
• Activated B lymphocytes undergo clonal expansion and functional specialization.
• They differentiate into antibody-secreting plasma cells and long-lived memory cells.

Differentiation of B Cells into Plasma Cells

• Activated B lymphocytes enlarge and transform into plasma cells.
• This transformation involves significant structural and functional changes.
• Plasma cells possess abundant rough endoplasmic reticulum for antibody synthesis.
• The enlarged intermediate stage is referred to as a B immunoblast.
• Cytokine signals from helper T lymphocytes facilitate this transformation.
• Plasma cells produce large quantities of specific antibodies for antigen elimination.
• Memory B cells ensure rapid and enhanced responses during subsequent exposures.

Proliferation of Plasma Cells and Antibody Production

• Activated B lymphocytes differentiate into antibody-secreting plasma cells.
• These cells undergo rapid clonal expansion, producing large numbers of identical cells.
• Each clone is specific to a particular antigen.
• This process is termed clonal selection.
• Plasma cells synthesize and release large quantities of specific antibodies.
• These antibodies bind and neutralize target antigens effectively.

Killing of the Invaders

• Antibodies eliminate antigens through multiple coordinated mechanisms.
• They neutralize toxins by binding to harmful molecules and preventing cellular damage.
• Antibodies can immobilize microbes, limiting their movement and spread within tissues.
• The antigen–antibody complex activates the complement system, leading to cell lysis and pathogen destruction.
• Antibodies promote agglutination and precipitation, converting soluble antigens into larger complexes.
• These complexes are more easily recognized and removed by phagocytic cells.
• Opsonization enhances phagocytosis by coating microbes with antibodies and complement proteins.
• This process increases the efficiency of ingestion and destruction by macrophages and neutrophils.
• Immunoglobulin G crosses the placenta and provides passive immunity to the fetus.
• Immunoglobulin A in breast milk protects mucosal surfaces in newborns.
• These mechanisms collectively ensure effective removal of pathogens and toxins from the body.

Formation of Memory B Cells and Subsequent Immunological Responses

• A small proportion of activated B lymphocytes differentiates into memory B cells.
• This process differs from blast transformation and involves long-term functional adaptation.
• Memory B cells usually remain in a resting state until re-exposure to the same antigen.
• Upon subsequent exposure, they produce a rapid and strong response.
• The secondary immune response is more intense and prolonged than the primary response.
• These cells enhance antibody production with higher specificity and affinity.
• Memory B cells are long-lived, often persisting throughout the individual’s lifetime.

Types of Humoral Immune Responses

• Humoral immune responses are classified into primary response and secondary response.

Primary Response

• It occurs when an antigen enters the body for the first time.
• Antibody production begins after a latent period of about 4 days to 4 weeks.
• The rise in antibody concentration is gradual and reaches a relatively low peak.
• Immunoglobulin M is the predominant antibody, with a smaller contribution from immunoglobulin G.
• The antibody titre declines within days to weeks after reaching its peak.
• This response helps initiate immunological memory but is less efficient.

Secondary Response

• It occurs on subsequent exposure to the same antigen.
• The response is rapid and more intense due to immunological memory.
• Memory B lymphocytes and T lymphocytes facilitate this enhanced response.
• Antibody production increases quickly, reaching a much higher peak concentration.
• Immunoglobulin G is the predominant antibody in this response.
• The antibody titre decreases slowly and remains elevated for a prolonged duration.
• This response provides stronger and longer-lasting protection against the antigen.

Complement System

• The complement system consists of plasma proteins that enhance antibody-mediated destruction of antigens.
• It includes more than 30 proteins, with key components designated as C1 to C9.
• Component C1 is subdivided into C1q, C1r, and C1s, making eleven major functional units.
• These proteins circulate in blood in an inactive form under normal conditions.
• Upon activation, they act as enzymatic cascades.
• They promote inflammation, opsonization, and lysis of pathogens.
• The complement system strengthens the effectiveness of the humoral immune response.

Mechanisms of Activation of Complement System

• The complement system is activated through three pathways: classical, alternative, and mannose-binding lectin pathway.

Classical Pathway

• It is initiated when C1 binds to antigen–antibody complexes, mainly involving immunoglobulin G or immunoglobulin M.
• Activation follows an enzyme cascade, where one protein activates another sequentially.
• Activated C1 triggers C4 and C2, forming a complex that activates C3 and later C5.
• C3a, C4a, and C5a act as inflammatory mediators, promoting chemotaxis, mast cell degranulation, and vasodilation.
• C3b enhances opsonization, facilitating phagocytosis.
• C5b, along with C6 to C9, forms the membrane attack complex, leading to microbial lysis.
• This complex creates pores in microbial membranes, causing ion influx and osmotic destruction.

Alternative Pathway

• It is initiated directly on microbial surfaces without antibody involvement.
• Surface polysaccharides of microorganisms trigger activation of C3.
• Activated C3 further activates other complement proteins, including C5.
• Properdin stabilizes this pathway and enhances complement activation.
• This pathway provides rapid defense as part of innate immunity.

Mannose-binding Lectin Pathway

• It begins when lectin binds to mannose residues on microbial surfaces.
• This binding activates complement proteins in a cascade similar to the classical pathway.
• It functions independently of antibodies but leads to similar outcomes, including opsonization and lysis.
• This pathway links innate and adaptive immunity by enhancing immune cell activation.
• Overall, complement activation results in inflammation, enhanced phagocytosis, and direct destruction of pathogens.

Antibodies

• Antibodies are immunoglobulins produced by B lymphocytes in response to specific antigens.
• They bind precisely to antigenic determinants, ensuring high specificity of immune reactions.
• Antigen binding activates B cells and stimulates further antibody production.
• Each B cell possesses specific receptors that recognize a particular antigen.
• Activation of a specific B cell clone results in production of a monoclonal antibody.

Types of Antibodies

• There are five major classes: IgG, IgA, IgM, IgD, and IgE.
• Immunoglobulin G is the most abundant in plasma, approximately 1000 milligrams percent.
• Immunoglobulin A is present around 200 milligrams percent and is important in mucosal immunity.
• Immunoglobulin M, about 120 milligrams percent, is the first antibody produced during primary response.
• Immunoglobulin D and immunoglobulin E are present in smaller concentrations and have specialized roles.

Table 19.3: Characteristics of antibodies.

Feature	IgG	IgA	IgM	IgD	IgE
Structure	Monomer	Monomer (dimer in secretions)	Pentamer	Monomer	Monomer
Heavy chain	Gamma	Alpha	Mu	Delta	Epsilon
Molecular weight (kDa)	150	160–385	900	180	190
Plasma level (mg%)	1000	200	120	3	0.05–2
Half-life (days)	21	6	5	3	2
Complement activation	Yes	Limited	Strong	No	No
Placental transfer	Yes	No	No	No	No

Structure of Antibodies

• Antibodies are glycoproteins composed of four polypeptide chains: two identical heavy chains and two identical light chains.
• Heavy chains contain about 450 amino acids and determine the antibody class, while light chains contain about 220 amino acids.
• Light chains are of two types, kappa or lambda, but only one type is present in a single antibody molecule.
• Some antibodies contain additional polypeptide components, such as joining chains in polymeric forms.
• Carbohydrate groups are attached to heavy chains, contributing to structural stability.
• Chains are linked by disulfide bonds, forming a stable Y-shaped structure.
• A flexible hinge region between heavy chains allows movement for antigen binding.
• The tips of the chains form the variable region, which contains antigen-binding sites.
• This region ensures high specificity toward particular antigens.
• The remaining portions constitute the constant region, which mediates effector functions.
• Each antibody can bind two antigenic determinants due to its bivalent nature.

Functions of Antibodies

• Immunoglobulin G activates complement through the classical pathway and provides long-term protection.
• Immunoglobulin A protects mucosal surfaces and is present in secretions such as saliva, tears, and intestinal fluids.
• Immunoglobulin M is the first antibody produced and strongly activates complement.
• Immunoglobulin D functions mainly as a receptor for antigen recognition on B lymphocytes.
• Immunoglobulin E induces histamine release from mast cells and basophils and plays a role in allergic reactions.

Mechanisms Of Self-Recognition (Immunological Tolerance)

• Self-recognition is the ability of the immune system to distinguish self from non-self components.
• It is mediated by major histocompatibility complex molecules that present antigens to immune cells.
• Immunological tolerance refers to a state of unresponsiveness toward self-antigens.
• This prevents harmful autoimmune reactions.
• Tolerance develops through positive and negative selection of lymphocytes during maturation.
• These mechanisms ensure elimination or inactivation of self-reactive immune cells.

Negative Selection

• Negative selection occurs during T lymphocyte development in the thymus.
• T cells with receptors that strongly recognize self-peptide–major histocompatibility complex complexes are eliminated.
• T cells that do not react to self-antigens are retained for immune function.
• This process is essential for maintaining self-tolerance and preventing autoimmunity.

Clonal Deletion

• Self-reactive T and B lymphocytes are removed during early development.
• These cells undergo apoptosis, eliminating potentially harmful clones.
• This mainly occurs during fetal and early life stages in central lymphoid organs.
• As a result, self-reactive clones are absent in postnatal circulation.

Clonal Anergy

• Some self-reactive lymphocytes survive but become functionally inactive.
• These cells fail to respond to antigenic stimulation due to lack of proper signaling.
• Reduced receptor activity or absence of co-stimulatory signals contributes to this state.
• Regulatory mechanisms of the immune system help maintain this unresponsive state.
• Together, these mechanisms ensure that self-reactive lymphocytes do not initiate immune responses against the body’s own tissues.

Positive Selection

• Positive selection occurs in the thymus during T lymphocyte maturation.
• T cells capable of recognizing self major histocompatibility complex molecules are selected for survival.
• Cells that fail to recognize these complexes undergo apoptosis.
• This process ensures functional yet self-tolerant T lymphocytes for effective immune responses.

Applied Physiology

Organ Transplantation

• Organ transplantation involves replacing a diseased or damaged organ with a healthy one.
• It is commonly performed in conditions such as renal failure and liver failure.
• Frequently transplanted tissues include skin, kidney, bone, and liver.
• The recipient immune system identifies the graft as foreign tissue and may initiate rejection.
• Transplant rejection primarily involves activation of cell-mediated immunity.
• T lymphocytes recognize non-self antigens on the graft and trigger immune responses.
• The severity and speed of rejection depend on compatibility of major histocompatibility complex antigens.
• Better human leukocyte antigen matching improves graft survival and reduces rejection risk.

Types of Transplants

• Autograft involves transfer of tissue within the same individual.
• It is commonly used in skin grafting and is not rejected due to self-compatibility.
• Isograft refers to transplantation between genetically identical individuals, such as identical twins.
• It is also accepted without immune rejection.
• Allograft involves transplantation between individuals of the same species with different genetic makeup.
• It commonly triggers immune responses and requires immunosuppressive therapy.
• Rejection may be slower if donor and recipient are closely related.
• Xenograft involves transplantation between different species.
• It is rapidly rejected due to strong immunological differences.
• Xenografts may be used temporarily, such as biological dressings in burn management.
• Understanding these principles is essential for improving graft survival and clinical outcomes.

Prevention of Transplant Rejection

• Prevention of transplant rejection requires suppression of recipient immune responses against graft antigens.
• Immunosuppressive drugs such as azathioprine inhibit lymphocyte proliferation and reduce T cell activity.
• These drugs increase susceptibility to infections due to generalized immune suppression.
• Glucocorticoids decrease cytokine production, especially interleukin-2, thereby limiting T cell activation.
• Antilymphocyte globulins target T lymphocytes and reduce their functional activity.
• Calcineurin inhibitors such as cyclosporine and tacrolimus block transcription of interleukin-2, preventing T cell proliferation.
• Mammalian target of rapamycin inhibitors inhibit interleukin-2 receptor signaling and lymphocyte growth.
• Monoclonal antibodies selectively block immune cell activation pathways.
• Combination therapy is commonly used to improve graft survival while minimizing toxicity.

Monoclonal Antibodies

• Monoclonal antibodies are identical immunoglobulins produced from a single B lymphocyte clone.
• They show high specificity toward a single antigenic determinant.
• They are widely used in diagnosis, immunotherapy, and prevention of transplant rejection.

Method of Production

• An animal is immunized with a specific antigen to stimulate antibody-producing cells.
• Spleen B lymphocytes are isolated as a source of antibody-producing cells.
• These cells are fused with immortal myeloma cells to form hybridoma cells.
• Individual hybridoma cells are cloned to obtain a single cell line.
• Each clone produces a uniform and specific monoclonal antibody.
• These antibodies are harvested and purified for clinical and research use.

Uses of Monoclonal Antibody

• Monoclonal antibodies are used to measure drug levels in blood for therapeutic monitoring.
• They assist in diagnosis of infections, allergic conditions, and chronic diseases.
• They enable early detection of cancers through specific antigen identification.
• They are applied in targeted therapy, vaccine development, and prevention of transplant rejection.

Immunotherapy

• Immunotherapy enhances or modulates the immune system to treat diseases, especially malignancies and chronic infections.
• It aims to improve immune recognition and destruction of abnormal cells.

Cellular Immunotherapy

• Patient-derived cytotoxic T lymphocytes or natural killer cells are used.
• These cells are isolated and activated in vitro using interleukin-2.
• Activated cells, called lymphokine-activated killer cells, are reinfused into the patient.
• They directly destroy tumor cells and improve immune surveillance.

Cytokine Therapy

• Cytokines regulate immune responses and are used therapeutically.
• Interferons are effective in viral infections and certain malignancies.
• Interleukin-2 enhances proliferation and activation of T lymphocytes.
• These agents boost immune-mediated destruction of abnormal cells.

Antibody Therapy

• Monoclonal antibodies target specific antigens on tumor or immune cells.
• They help in selective destruction of malignant cells.
• They are also used to prevent transplant rejection by modulating immune responses.

Adjuvant Therapy

• Adjuvants are substances that enhance immune response to antigens.
• Examples include aluminum salts and microbial components.
• They stimulate macrophages and lymphocytes non-specifically.
• Adjuvants are widely used in vaccines to improve immunogenicity.
• However, they may produce delayed hypersensitivity reactions in some individuals.

Immunological Disorders

Allergy

• Allergy is an exaggerated immune response to usually harmless antigens.
• It involves activation of immunoglobulin E and release of inflammatory mediators.
• Allergic reactions are classified as local or systemic.

Local Allergy

• It is restricted to a specific tissue or region of the body.
• Common manifestations include urticaria, eczema, and localized swelling.

Systemic Allergy

• It affects multiple organ systems and is termed anaphylaxis.
• It may occur after exposure to drugs such as penicillin or local anesthetics.
• Severe reactions can lead to anaphylactic shock, requiring immediate medical intervention.

Hypersensitivity Reactions

• Hypersensitivity reactions are exaggerated immune responses causing tissue damage.
• They are classified into four types based on mechanism and mediators.

Type I Reaction or Anaphylaxis

• It is mediated by immunoglobulin E on mast cells and basophils.
• Re-exposure to allergen triggers release of histamine and other mediators.
• These cause vasodilation, increased vascular permeability, and bronchoconstriction.
• Severe cases lead to anaphylactic shock, a life-threatening emergency.

Type II Reaction or Cytotoxic Reaction

• It is mediated by immunoglobulin G or immunoglobulin M against cell surface antigens.
• This results in complement activation and cell destruction.
• Examples include incompatible blood transfusion and hemolytic disease of the newborn.

Type III Reaction or Immune Complex Disease

• Antigen–antibody complexes deposit in tissues and activate complement.
• This leads to inflammation and tissue injury.
• Common examples include glomerulonephritis, systemic lupus erythematosus, and rheumatoid arthritis.

Type IV Reaction or Cell Mediated Reaction or Delayed Hypersensitivity Reactions

• It is mediated by sensitized T lymphocytes rather than antibodies.
• Antigen presentation activates T cells, which release cytokines.
• Cytokines recruit macrophages and produce localized inflammation.
• The reaction develops slowly, usually within 24 to 72 hours.
• A typical example is the tuberculin skin test.

Autoimmune Diseases

• Autoimmune diseases occur when the immune system reacts against self-antigens.
• This results from loss of self-tolerance and failure to eliminate self-reactive lymphocytes.
• Persistence of autoreactive T cells and B cells leads to immune-mediated tissue damage.
• B lymphocytes produce autoantibodies directed against normal body components.
• These antibodies may destroy cells or alter receptor function.
• In myasthenia gravis, antibodies damage nicotinic acetylcholine receptors, causing muscle weakness.
• In Graves disease, antibodies stimulate thyroid-stimulating hormone receptors, causing excess hormone production.
• Common examples include systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, and myasthenia gravis.
• Early diagnosis and immunomodulatory therapy are important for disease control.

Immunodeficiency States

• Immunodeficiency states are conditions with impaired immune function, increasing susceptibility to infections and malignancies.
• They are classified into primary (congenital) and secondary (acquired) types.

Congenital Immunodeficiency Syndromes

• Severe combined immunodeficiency involves defective development of T lymphocytes, causing impaired cellular immunity.
• In some forms, both T and B lymphocyte development is affected, leading to combined immune deficiency.
• X-linked agammaglobulinemia results from failure of B cell maturation, causing markedly reduced antibody levels.
• Deficiency of major histocompatibility complex class two molecules leads to reduced helper T lymphocytes.
• These disorders present early in life with recurrent, severe infections.

Acquired Immunodeficiency Syndrome (AIDS)

• The most important example is acquired immunodeficiency syndrome, caused by human immunodeficiency virus infection.
• The virus targets CD4-positive T lymphocytes, leading to progressive immune suppression.
• Loss of helper T cell function impairs both humoral and cellular immunity.
• Patients develop recurrent opportunistic infections and certain malignancies.
• Common infections include candidiasis, tuberculosis, and pneumocystis pneumonia.
• Clinical features include prolonged fever, lymph node enlargement, chronic diarrhea, and weight loss.
• Kaposi sarcoma is a characteristic associated malignancy.
• Transmission occurs through sexual contact, contaminated blood, or vertical transmission.
• Management includes antiretroviral therapy to reduce viral replication and improve immune function.
• Early diagnosis and preventive care are essential to reduce morbidity and mortality.

Cytokines

• Cytokines are small regulatory proteins that act mainly in a paracrine manner to control immune responses.
• They are secreted by lymphocytes, macrophages, endothelial cells, and other tissues.
• Major groups include interleukins, tumor necrosis factors, interferons, transforming growth factors, and granulocyte macrophage colony-stimulating factor.

Interleukins

• Interleukins are produced by immune and somatic cells.
• They regulate proliferation and differentiation of B and T lymphocytes.
• They support hematopoiesis, including leukocyte and platelet production.
• Interleukin-1 induces fever, increases neutrophil count, and enhances inflammatory responses.

Tumor Necrosis Factors (TNFs)

• Tumor necrosis factor alpha is produced mainly by activated macrophages.
• It promotes inflammation, vascular changes, and tumor cell destruction.
• Tumor necrosis factor beta is produced by T lymphocytes and has similar effects.

Interferons (IFN)

• Interferon alpha and beta have strong antiviral activity and enhance innate immunity.
• They increase expression of major histocompatibility complex molecules.
• Interferon gamma activates macrophages and promotes cellular immunity.
• It also enhances antigen presentation and immune defense.

GM-CSF

• It stimulates bone marrow to produce granulocytes and macrophages.
• It supports recovery of immune cells during infections or after chemotherapy.
• Overall, cytokines coordinate immune responses, inflammation, and cell growth.

Table 19.4: Source and important functions of common cytokines.

Cytokine	Major Source	Primary Targets	Key Physiological Actions
IL-1	Macrophages, endothelial cells	Multiple cell types	Initiates inflammation, induces fever, promotes acute phase proteins, and enhances leukocyte adhesion and migration
IL-2	Helper T lymphocytes	T lymphocytes	Stimulates T cell proliferation and enhances cellular immunity
IL-3	T lymphocytes	Bone marrow progenitors	Promotes hematopoiesis and growth of precursor cells
IL-4	Helper T2 cells, mast cells	B lymphocytes	Induces antibody production and immunoglobulin E class switching
IL-5	Helper T2 cells, eosinophils	Eosinophils	Stimulates eosinophil growth and activation
IL-6	Macrophages, fibroblasts	B and T cells, liver	Promotes lymphocyte differentiation and acute phase protein synthesis
IL-8	Macrophages, endothelial cells	Neutrophils	Acts as a chemotactic factor and promotes migration of neutrophils
IL-12	Macrophages, dendritic cells	T cells, natural killer cells	Enhances interferon gamma production and cellular immunity
IL-17	Activated T lymphocytes	Epithelial and endothelial cells	Promotes inflammation and recruitment of neutrophils
TNF-α	Macrophages, T cells	Most tissues	Induces inflammation, fever, and endothelial activation
TNF-β	T lymphocytes	Various cells	Contributes to inflammatory responses
Interferon-α/β	Virus-infected cells	Neighboring cells	Provides antiviral defense and inhibits viral replication
Interferon-γ	T cells, natural killer cells	Immune cells	Activates macrophages and enhances antigen presentation
TGF-β	T and B lymphocytes	Immune cells	Suppresses immune responses and regulates inflammation
GM-CSF	T cells, macrophages	Bone marrow cells	Stimulates production of granulocytes and macrophages
Monocyte chemoattractant protein-1	Fibroblasts, monocytes	Monocytes, T cells	Recruits immune cells to sites of inflammation
Eotaxin	Lung and cardiac cells	Eosinophils	Attracts eosinophils in allergic reactions
Platelet factor-4	Platelets	Endothelial cells	Modulates inflammation and inhibits cell proliferation