Principles of Host Response: Immunology
Introduction to Immunity
Two primary ways to divide immunity:
Innate immunity
The body's first line of defense; it is a "built-in", non-specific mechanism that does not require prior exposure to antigens.
Provides an immediate response, typically within minutes to hours.
Components include physical barriers (skin, mucous membranes), chemical barriers (acidic pH, antimicrobial peptides), cellular components (phagocytes like macrophages and neutrophils, and Natural Killer cells), and soluble factors (complement proteins, cytokines).
Recognizes pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), leading to a rapid, generalized response.
Initiates and influences the inflammatory response.
Adaptive immunity
Also known as acquired or specific immunity, it is highly specific and requires prior exposure to a particular antigen to develop.
Characterized by specificity, diversity, memory, and self/non-self recognition.
Primarily mediated by specialized lymphocytes (T-cells and B-cells).
The initial response is slower compared to innate immunity, taking days to weeks, but subsequent responses are faster and stronger due to immunologic memory.
Immune Mechanisms: Basis of Response
Basis of Immune response: The presence of an antigen (Ag) that the body recognizes as "foreign" or "non-self."
Antigens: These are molecules (typically proteins but can also be polysaccharides, lipids, or nucleic acids) that can elicit an immune response.
Specific regions on antigens, called epitopes (or antigenic determinants), are the actual sites to which antibodies or T-cell receptors bind.
Triggers the response: T-cells and B-cells work cooperatively, often with the help of antigen-presenting cells (APCs), to mount a highly specific response against a particular antigen.
Determination of "self" versus "non-self" / "foreign":
Human Leukocyte Antigens (HLA), also known as Major Histocompatibility Complex (MHC) proteins, are unique sets of "self" antigens expressed on the surface of an individual's cells.
They play a crucial role in antigen presentation to T-cells.
Class I HLA (MHC I): Found on platelets and all nucleated cells (e.g., virtually all body cells except red blood cells).
Presents endogenous peptides (peptides derived from proteins synthesized within the cell, like viral proteins or tumor antigens) to CD8+ cytotoxic T-cells.
Class II HLA (MHC II): Found primarily on professional antigen-presenting cells (APCs) such as B-cells, macrophages, and dendritic cells, as well as some T-cells.
Presents exogenous peptides (peptides derived from proteins taken up by the cell from its external environment, like bacterial components) to CD4+ helper T-cells.
No two individuals (except for identical twins) possess identical HLA antigens, making them critical for transplant compatibility.
During embryonic development, lymphocytes capable of reacting strongly to an individual's "self" antigens are identified through processes called positive and negative selection and are typically destroyed or inactivated (clonal deletion/anergy).
This destruction or inactivation process "programs" the immune system to recognize and tolerate "self," preventing autoimmunity.
Components of the Immune System: Organs
Major Lymphoid Organs: Bone Marrow
The primary hematopoietic organ where all blood cells, including lymphocytes, originate from multipotent hematopoietic stem cells.
These stem cells give rise to three distinct lymphocyte lineages:
T-lymphocytes (precursors)
B-lymphocytes (complete maturation and programming)
Natural Killer (NK) cells (complete maturation and programming)
Bone marrow is also the primary site for the programming and maturation of B-cells to recognize "self" versus "non-self" antigens, primarily through the expression of appropriate B-cell receptors (BCRs).
Major Lymphoid Organs: Thymus
A bilobed organ located in the mediastinum, superior to the heart.
The thymus is the site where T-cell precursors migrate from the bone marrow and undergo a complex maturation process, including positive and negative selection, to become immunocompetent T-cells.
Positive selection: Ensures T-cells can recognize self-MHC molecules.
Negative selection: Eliminates T-cells that react too strongly to self-antigens presented by self-MHC, thus preventing autoimmunity.
Failure of the thymus to develop properly (e.g., in DiGeorge Syndrome) leads to severe immunodeficiency, particularly affecting T-cell-mediated immunity.
The thymus grows until puberty, after which it undergoes normal progressive involution (atrophy), replaced by adipose tissue, though it remains functional to some degree throughout life.
Other Major Lymphoid Organs
Both mature T- and B-lymphocytes, as well as NK cells, enter the vascular and lymphatic systems, populating secondary lymphoid organs and tissues.
These peripheral organs and tissues serve as sites where immune responses are initiated and effector cells are generated.
These include:
Lymph nodes: Small, encapsulated organs strategically located throughout the lymphatic system. They filter lymphatic fluid, trapping antigens and facilitating interactions between APCs, T-cells, and B-cells to initiate adaptive immune responses.
Spleen: The largest secondary lymphoid organ, it filters blood, removing old red blood cells and pathogens. It is a key site for initiating immune responses against blood-borne antigens.
"Mucosa-associated lymphoid tissue" (MALT): A diffuse system of lymphoid tissues found in the mucous membranes lining the respiratory, gastrointestinal, and genitourinary tracts. It is specialized to respond to antigens encountered at mucosal surfaces.
MALT includes structures like tonsils and adenoids (Waldeyer's ring), Peyer's patches in the small intestine, and lymphoid aggregates in the bronchi (BALT - Bronchus-associated lymphoid tissue).
These peripheral organs and tissues function to identify and process "non-self" (foreign) antigens, enabling an efficient and targeted immune response to be mounted.
Components of the Immune System: Cells (Lymphocytes)
Lymphocyte Classification (General)
T and B lymphocytes are morphologically similar and cannot be differentiated under a standard light microscope.
However, they possess:
Distinct cell surface markers/antigens (cluster of differentiation, CD markers) that are specific to their lineage and maturation stage.
Distinct cell functions in the adaptive immune response.
Distinguishing techniques: Special immunophenotyping techniques, such as flow cytometry, are used to identify unique cell surface antigens based on fluorescent antibody staining.
Importance: This classification is crucial for diagnosing different types of lymphoproliferative disorders (e.g., leukemias, lymphomas) and various immunodeficiency conditions (e.g., AIDS, SCID) by assessing lymphocyte subsets and numbers.
T-lymphocytes (T-cells)
Constitute the majority (75-80 ext{%}) of circulating lymphocytes in peripheral blood.
Programmed: Programmed and mature in the thymus, where they acquire unique antigen-specific T-cell receptors (TCRs) and co-receptors (CD4 or CD8).
Function: Mediate the cellular immune response, directly engaging with target cells or regulating the activity of other immune cells (B-lymphocytes, macrophages, and other T-cells) through cytokine secretion.
T-lymphocyte subsets:
T-helper cells (CD4+):
Recognize antigens presented by MHC Class II molecules on APCs.
Are crucial "orchestrators" of the immune response, assisting both B-cells in producing antibodies (by stimulating B-cell proliferation and differentiation through cytokine release and direct contact) and enhancing the activity of cytotoxic T-cells and macrophages.
Play a central role in both humoral and cell-mediated immunity.
T-suppressor/cytotoxic cells (CD8+):
Recognize antigens presented by MHC Class I molecules on target cells.
Directly attack and kill cells presenting foreign antigens (e.g., virally-infected cells, tumor cells) through mechanisms like perforin and granzyme release, which induce apoptosis in the target cell.
Also play a role in suppressing excessive or inappropriate immune responses (regulatory T-cells, a subset of CD4+ or CD8+ cells, help maintain self-tolerance).
Are active in organ transplant rejection.
T-memory cells:
Long-lived lymphocytes that persist after an initial exposure to an antigen.
Confer life-long memory of specific antigens, allowing for a much faster, stronger, and more efficient secondary immune response upon re-exposure to the same antigen.
This rapid recall response averts the initial time delay required for antigen processing and primary activation.
B-lymphocytes (B-cells)
Comprise approximately 10-15 ext{%} of circulating lymphocytes.
Programmed: Programmed and mature in the bone marrow, where they express unique B-cell receptors (BCRs), which are surface-bound immunoglobulins, typically IgM and IgD, specific for a particular antigen.
Response to antigenic challenge (often with T-cell help for protein antigens): Upon encountering their specific antigen and receiving T-helper cell signals (for most protein antigens), these cells can either:
Mature into plasma cells: Highly specialized, antibody-secreting factories capable of producing large quantities of soluble antibodies (immunoglobulins) specifically directed against that antigen.
Become memory B-cells: Long-lived cells that provide a faster, more robust, and higher-affinity antibody response upon subsequent re-exposure to the specific antigen.
Natural Killer (NK) Cells
Account for about 5-10 ext{%} of circulating lymphocytes.
Function: Part of the innate immune response, their function is not dependent on prior antigen processing and stimulation or MHC presentation.
Mechanism: Directly cytotoxic.
They recognize and bind to "foreign" or abnormal cells (e.g., virally-infected cells, tumor cells, and some stressed cells that have reduced or absent MHC Class I expression).
They lyse their cell membranes through the release of cytotoxic granules containing perforin and granzymes, similar to CD8+ T-cells.
Their activity is regulated by a balance of activating and inhibitory receptors that recognize ligands on target cells.
Importance: Significant in early defense against viral infections, immune surveillance against tumor cells, and can contribute to transplant rejection.
The Adaptive Immunologic Response
Antigen Processing and Presentation
Initial exposure: "Foreign" antigens are first encountered and then processed and presented by professional Antigen Presenting Cells (APCs), such as macrophages, dendritic cells, and B-cells.
APCs:
They internalize antigens (via phagocytosis or endocytosis), break them down into smaller peptide fragments.
These processed peptide fragments are then loaded onto MHC Class I or Class II molecules and displayed on the APC's cell surface.
This presentation allows T- and B-lymphocytes, which have receptors already programmed to recognize these specific foreign antigens, to be activated.
Outcome: This interaction leads to the activation of specific T-lymphocytes (initiating a cellular immune response) and/or activation of B-lymphocytes that mature into plasma cells (initiating a humoral immune response).
These activated cells and antibodies are highly specific, directed against particular regions (epitopes) of the antigens.
Most protein antigens typically stimulate both arms of the adaptive immune response (cellular and humoral), demonstrating the interconnectedness of these systems.
Immune Responses: Cell-Mediated vs. Humoral
Cell-Mediated Immune Response (CMIR):
Primarily targets intracellular pathogens (e.g., viruses, some bacteria residing inside cells), fungi, some parasites, and tumor cells. It is also critical in transplant rejection.
Antigen is processed by an APC (e.g., macrophage) and presented via MHC Class I or II to specific T-lymphocytes.
This evokes the production of "activated" T-cells, particularly cytotoxic T-cells (CD8+) that directly attack infected or abnormal cells, and helper T-cells (CD4+) that secrete cytokines to coordinate the response.
These cytotoxic T-cells directly attack and bind to cells presenting that specific antigen on MHC Class I, inducing their destruction.
Humoral Immune Response (HIR):
Primarily targets extracellular pathogens (e.g., bacteria, extracellular viruses, toxins) and is mediated by antibodies circulating in the blood and lymph.
Antigen is processed by an APC (e.g., B-cell acting as an APC) and presented, often with T-helper cell activation.
This evokes the production of circulating antibodies (immunoglobulins) specific to that antigen, secreted by plasma cells.
Antibodies neutralize pathogens, activate complement, and promote phagocytosis.
Humoral Immune Response: Antibodies (Immunoglobulins)
What are antibodies?
Glycoproteins of the immunoglobulin (Ig) class, produced and secreted by plasma cells in response to specific antigens.
Also commonly known as "gamma globulins" due to their migration pattern in electrophoresis.
Their primary function is to recognize and bind to specific antigens, leading to their neutralization or elimination.
Antibody Structure
Basic structure: All immunoglobulins have a fundamental Y-shaped monomeric structure composed of four polypeptide chains.
Two identical heavy chains (H chains), which determine the antibody class (IgM, IgG, IgA, IgE, IgD).
Two identical light chains (L chains), of which there are two types (kappa and lambda).
These chains are held together by interchain disulfide bonds.
Constant portions (Fc region):
Both light chains and heavy chains possess a constant region, characterized by a relatively "constant" amino acid sequence at their carboxy (C-terminal) end within a given immunoglobulin class.
The constant region of the heavy chains constitutes the Fc (fragment crystallizable) portion of the antibody, which dictates the main biologic activity and effector functions of the antibody.
It subclassifies the heavy chains into five distinct classes (isotypes): mu (\mu) for IgM, gamma (\gamma) for IgG, alpha (\alpha) for IgA, epsilon (\epsilon) for IgE, or delta (\delta) for IgD.
The Fc portion also binds to specific Fc receptors (FcRs) expressed on various immune cells (e.g., macrophages, neutrophils, NK cells, mast cells), triggering different effector functions.
Furthermore, Fc portions, particularly of IgM and IgG, can initiate the complement cascade (a system of several plasma proteins activated sequentially to destroy cells, opsonize pathogens, and serve as an important source of inflammatory mediators).
The hinge region, a flexible segment within the heavy chain, connects the Fab arms to the Fc portion, allowing flexibility in antigen binding.
Variable portions (Fab region):
Each light chain and heavy chain has a region with highly variable amino acid sequencing at their amino (N-terminal) end. This region forms the antigen-binding site.
This high variability allows for the enormous diversity and antigen specificity of antibodies.
The Fab (fragment antigen-binding) portion of the immunoglobulin (composed of one light chain and a portion of one heavy chain) serves as the antigen-binding site, specifically interacting with and binding to particular epitopes on antigens.
In essence, the variable (Fab) region determines "What antigen does it match?" while the constant (Fc) region dictates "Where's it going to take the Ag?" and what effector mechanisms will be activated.
Classes of Immunoglobulin
There are five main antigenically distinct kinds of heavy chains, forming the basis of five classes (isotypes) of antibodies: IgM, IgG, IgA, IgE, and IgD.
Each class possesses different structural properties, distribution in the body, and mediates distinct immune responses and effector functions.
IgM:
Typically exists as a pentamer (five basic Ig units linked by a J chain) when secreted, making it a large molecule with 10 antigen-binding sites.
It is the first antibody produced during a primary immune response against a new antigen, appearing early in infection.
Can efficiently agglutinate (clump) antigens and is a potent activator of the classical complement pathway, which culminates in the formation of the membrane attack complex (MAC) that can lyse cell walls.
Monomeric IgM also serves as the major B-cell receptor (BCR).
IgG:
The most abundant antibody in circulation (approx. 75-80 ext{%} of total Ig), existing as a monomer.
The only antibody capable of crossing the placenta, providing crucial passive immunity to the fetus and newborn (neonatal immunity).
Attaches to inflammatory cells (macrophages, neutrophils, NK cells, eosinophils) via its Fc portion (Fc\gamma receptors), facilitating opsonization and antibody-dependent cell-mediated cytotoxicity (ADCC).
Can serve as an opsonin, coating pathogens and enhancing their binding for phagocytosis by phagocytic cells.
Important in secondary immune responses and long-term protection.
IgA:
Typically a dimer of the basic Ig structure (two Ig units linked by a J chain and a secretory component) in secretions, and a monomer in serum.
Predominant in both blood and mucosal secretions (known as "secretory IgA") such as those found in airways, gastrointestinal tract, tears, saliva, breast milk, and urogenital tract.
Helps protect against mucosal invasion by microorganisms by neutralizing pathogens at entry sites and preventing their attachment to epithelial cells.
IgE:
Exists as a monomer.
Does not circulate freely in significant amounts in the blood but is found primarily in tissues, where its Fc portion binds with high affinity to Fc\epsilon receptors on the surface of mast cells and basophils.
Mast cells and basophils contain granules rich in inflammatory mediators, especially histamine.
When IgE on the surface of these cells recognizes and binds an antigen, it triggers the degranulation of mast cells/basophils, leading to the rapid release of histamine and other mediators, thereby mediating allergic reactions (Type I hypersensitivity) and immune responses to parasites.
IgD:
Exists as a monomer.
Its function is not precisely well understood, but it is primarily found on the surface membranes of naive B-lymphocytes, where it acts as a B-cell receptor (BCR) along with monomeric IgM.
May play a role in the activation, development, and maturation of the humoral immune system, particularly in signaling B-cell activation.
Antibody Response and Immunologic Memory
Primary B-cell response to antigenic challenge:
After the first exposure to a novel antigen, there is a lag phase of several days.
IgM is the first antibody produced, appearing after the lag, reaching a peak within roughly two weeks, then declining.
Antigen-specific IgG antibodies appear slightly later (around day 10 or more), reach a higher peak, and remain at a high level for a longer period, indicating a shift from IgM to IgG production (isotype switching).
Immunologic Memory (Anamnestic/Booster Response or Secondary Immune Response):
Refers to the rapid, increased, and qualitatively superior production of antibodies (and activated T-cells) upon a second or subsequent exposure to the same antigen.
This accelerated response is mediated by long-lived memory T- and B-cells produced after the first exposure.
Memory cells enable the immune response to:
React rapidly (shorter lag phase).
Produce significantly greater quantities of antibody (higher magnitude of response), primarily IgG, with higher affinity for the antigen.
Be more sustained.
Pathology Involving the Immune System
Organ Transplant/Graft Rejection
The immune system must be vigorously suppressed in transplant patients to prevent recognition of donor HLA/MHC antigens as foreign, which, in turn, significantly increases the recipient's risk for severe infections and certain malignancies.
Types of Rejection:
Hyperacute rejection:
Caused by preformed antibodies (typically IgM) in the recipient against donor tissue antigens (e.g., ABO blood group antigens or HLA antigens from prior transfusions/pregnancies).
Occurs within minutes to hours of transplantation, immediately upon reperfusion of the graft.
Pathology includes diffuse intravascular coagulation, fibrinoid necrosis of vessels, prominent thrombosis (blood clots), and severe acute inflammation, leading to rapid graft failure.
This type of rejection is now rare due to pre-transplant cross-matching.
Acute rejection:
Primarily mediated by both cell-mediated (T-cell-driven) and, to a lesser extent, humoral (antibody-mediated) immune responses directed against donor MHC antigens.
Occurs typically days, weeks, or even months following transplantation, usually within the first year.
Lymphocytes (CD4+ and CD8+ T-cells) react to foreign MHC antigens; cytotoxic T-cells directly attack and damage graft cells, and helper T-cells encourage both other T-cell responses and a B-cell (antibody) response.
Pathological features include lymphocytic infiltrates in the graft parenchyma and/or vasculitis.
Chronic rejection:
Develops insidiously over months to years post-transplant and is largely mediated by cellular responses, but humoral immunity also plays a significant role.
Characterized by chronic vascular damage, progressive fibrosis, and arteriosclerosis (thickening of vessel walls due to intimal proliferation) within the graft, leading to gradual loss of graft function.
This is often a major cause of long-term graft failure despite immunosuppression.
Immune Deficiency Diseases
Conditions characterized by an impaired ability to mount an effective immune response, leading to increased susceptibility to infections and sometimes cancer.
Thymic Aplasia (DiGeorge Syndrome):
A primary immunodeficiency caused by embryologic failure of the third and fourth pharyngeal pouches to develop, leading to a congenital absence or severe hypoplasia of the thymus and parathyroid glands.
T-cells never properly mature (as the thymus is crucial for T-cell development), leading to a profound inability to develop a T-lymphocyte (cellular) immune response.
Because T-helper cells (CD4+) are critical for activating B-cells, antibody production (humoral immunity) is also significantly impaired or absent, especially for T-dependent antigens.
Patients are highly vulnerable to severe recurrent viral, fungal, and intracellular bacterial infections, as well as hypocalcemia from parathyroid aplasia.
Infantile (Bruton) Agammaglobulinemia:
A rare, X-linked recessive primary immunodeficiency, predominantly affecting males.
Characterized by a defect in B-cell tyrosine kinase (BTK) enzyme, leading to a failure of B-cell maturation beyond the pre-B-cell stage.
Results in a severe deficiency of mature B-cells and a profound failure of the humoral immune response, with significantly reduced or absent quantities of all classes of immunoglobulins (Igs).
T-cell immunity is typically normal.
Patients are highly vulnerable to severe recurrent bacterial infections (especially encapsulated bacteria) but generally handle viral and fungal infections well.
Alymphocytic Agammaglobulinemia (Severe Combined Immunodeficiency - SCID):
A group of severe primary immunodeficiencies caused by diverse genetic defects in the lymphocyte stem cell population or early lymphocyte development pathways (e.g., adenosine deaminase deficiency, X-linked SCID due to common gamma chain defect).
Results in a marked decrease or absence of both T and B-lymphocytes (hence "combined" immunodeficiency).
Associated with thymic hypoplasia and poorly developed lymphoid tissues.
Patients lack both humoral and cellular immune mechanisms, making them extremely susceptible to all types of infections (bacterial, viral, fungal, protozoal) and opportunistic pathogens.
Without aggressive treatment, such as bone marrow transplantation or gene therapy, death usually occurs early in childhood from recurrent severe infections.
Acquired Immunodeficiency Syndrome (AIDS):
Caused by the Human Immunodeficiency Virus (HIV), a retrovirus that primarily infects and destroys lymphocytes, specifically T-helper cells (CD4+ cells), which are crucial for coordinating both humoral and cellular immunity.
Monocytes/macrophages and dendritic cells may also become infected, serving as reservoirs for the virus.
Leads to a progressive and profound defect in both humoral and cellular immunity.
CD4 to CD8 ratio:
In normal individuals, the ratio of CD4 (T-helper) to CD8 (T-suppressor/cytotoxic) cells in the blood is approximately 2:1 (1.5-2.5:1).
In individuals with AIDS, due to the progressive destruction of CD4+ cells, this ratio is typically inverted, falling to <1 (often <0.5).
This marked decrease in CD4 cell counts makes patients highly susceptible to a wide variety of opportunistic infections (e.g., Pneumocystis pneumonia, Kaposi's sarcoma, Mycobacterium avium complex) and unusual malignancies.
Also an increased incidence of lymphoid malignancies (e.g., B-cell lymphomas) and other cancers.
Hypersensitivity Reactions
Defined as overly exuberant or inappropriate immune responses that produce tissue injury and disease in the host rather than protection.
Four categories based on the mechanism of tissue damage (Gell and Coombs classification):
Types I, II, and III are immediate hypersensitivity reactions, involving the humoral immune response (B-cells and antibodies).
Type IV is a delayed hypersensitivity reaction, involving the cell-mediated immune response (T-cells and macrophages).
Type I Hypersensitivity (Anaphylaxis/Atopy - Immediate):
Also known as allergic or anaphylactic hypersensitivity.
Most common in individuals predisposed to allergies (atopy) in tissues exposed to external antigens (skin, respiratory tract, GI tract).
First exposure to antigen (sensitization): No symptoms, but B-cells (with T-helper cell assistance) produce specific IgE antibodies.
These IgE antibodies have a high affinity for and bind to the Fc\epsilon surface membrane receptors densely expressed on mast cells (in tissues) and basophils (in blood).
This sensitizes the mast cells/basophils.
Second exposure to antigen (effector phase): The antigen (allergen) re-enters the body and cross-links the IgE antibodies bound to the surface of sensitized mast cells and basophils.
This cross-linking triggers the immediate degranulation of mast cells and basophils, releasing preformed mediators (e.g., histamine, serotonin, proteases) and newly synthesized mediators (e.g., leukotrienes, prostaglandins, platelet-activating factor, cytokines).
These mediators initiate a typical allergic response, including vasodilation, increased vascular permeability, smooth muscle contraction (bronchospasm, gut hypermotility), interstitial edema, and an influx of eosinophils.
Examples: Atopic dermatitis (eczema), urticaria (hives), allergic rhinitis (hay fever), allergic asthma, food allergies (e.g., peanut allergy).
Life-threatening anaphylaxis: A severe, systemic form of Type I reaction, characterized by widespread vasodilation, profound hypotension, bronchospasm, laryngeal edema, and shock. Can occur from bee stings, intravenous injection of certain anesthetics, or radiographic contrast material, requiring immediate epinephrine.
Type II Hypersensitivity (Cytotoxic/Cytolytic - Immediate):
Mediated by circulating antibodies (primarily IgG and IgM) that specifically attack antigens that are intrinsically bound to (or are a component of) another cell's membrane or extracellular tissue (e.g., basement membrane).
The antigen-antibody interaction promotes the destruction or dysfunction of the target cell or tissue through several mechanisms:
Activation of the classical complement pathway: Leading to cell lysis by MAC formation or opsonization and phagocytosis.
Opsonization: Antibodies coating target cells enhance their phagocytosis by macrophages and neutrophils that have Fc receptors.
Antibody-dependent cell-mediated cytotoxicity (ADCC): NK cells can bind to the Fc portion of antibodies bound to target cells, leading to killing of the target cell without prior sensitization.
Examples: Autoimmune hemolytic anemias, immune thrombocytopenic purpura, goodpasture syndrome (antibodies against basement membranes in lung and kidney), erythroblastosis fetalis (Rh incompatibility), blood transfusion reactions (ABO incompatibility), and certain drug-induced hemolytic reactions.
Type III Hypersensitivity (Immune Complex Disease - Immediate):
Formation of immune complexes: Introduction of an antigen triggers the production of antibodies that form soluble antigen-antibody (immune) complexes in the circulation.
Normally, small, soluble immune complexes are efficiently cleared by phagocytic cells.
Deposition of immune complexes: Under pathologic conditions (e.g., persistent antigen exposure, insufficient phagocytic clearance, or formation of intermediate-sized complexes), these antigen-antibody complexes become deposited in various tissues.
This deposition often favors filtering tissues with high blood flow and porous capillaries like renal glomerular capillaries, blood vessel walls (vasculitis), and serosal surfaces of joints (synovitis).
Immune complex deposition can be localized (e.g., Arthus reaction, farmer's lung) or disseminated throughout the body (systemic diseases).
Tissue injury: Complexes stuck in tissues activate the classical complement cascade, leading to the recruitment and activation of neutrophils and macrophages. These cells release lysosomal enzymes and reactive oxygen species, initiating an acute inflammatory reaction and widespread tissue damage.
Examples: Post-infectious glomerulonephritis (e.g., post-streptococcal), systemic lupus erythematosus (SLE), immune vasculitis (e.g., polyarteritis nodosa), serum sickness, and some forms of rheumatoid arthritis.
Type IV Hypersensitivity (Cell-Mediated or Delayed Hypersensitivity - DTH):
Unlike the other types, this reaction does not involve antibodies but is mediated solely by T-lymphocytes (primarily CD4+ helper T-cells and CD8+ cytotoxic T-cells) and macrophages.
The reaction takes 24-72 hours to develop after antigen exposure, hence "delayed."
After macrophage processing and presentation of the antigen (via MHC Class II for CD4+ T-cells), the antigen reacts with specifically "activated" T-lymphocytes that have been previously sensitized.
Activated T-cells proliferate and release cytokines (e.g., interferons, interleukins), which recruit and activate macrophages at the site of antigen exposure.
Activated macrophages transform into 'epithelioid' cells, which may fuse to form multinucleated giant cells. The sustained inflammatory response often results in granulomatous inflammation.
Examples: Tuberculin (TB) skin tests (PPD test), contact dermatitis (e.g., poison ivy, nickel allergy), sarcoidosis, chronic transplant rejection (aspects of it), and many "autoimmune" diseases like Type 1 diabetes and multiple sclerosis.
Autoimmune Diseases
Problem: The immune system incorrectly interprets the host's own "self" antigens as "foreign" antigens, leading to an immune response that attacks and damages healthy tissues.
Examples:
Organ or tissue specific diseases: Affect a single organ or tissue type. Examples include Autoimmune hemolytic anemia (red blood cells), Hashimoto's thyroiditis (thyroid gland), Graves' disease (thyroid gland), Type 1 diabetes mellitus (pancreatic beta cells), and rheumatoid arthritis (joints, though can be systemic).
Systemic diseases: Affect multiple organs and tissues throughout the body. Examples include Systemic lupus erythematosus (SLE - affects skin, joints, kidneys, heart, lungs, brain), progressive systemic sclerosis (scleroderma - affects skin, blood vessels, internal organs), and Sjögren's syndrome (exocrine glands, particularly salivary and lacrimal).
Most autoimmune diseases demonstrate circulating autoantibodies and/or sensitized autoreactive T-cells, which may be directed against almost any circulating or tissue antigen recognized as "foreign."
The etiology is complex and multifactorial, involving a combination of genetic susceptibility (e.g., certain HLA alleles) and environmental factors (e.g., infections, toxins).
Autoimmunity: Possible Causes
Clonal deletion failure: During normal T-cell and B-cell development in the thymus and bone marrow, lymphocytes that are strongly reactive to "self" antigens should ideally be eliminated (negative selection or clonal deletion) or rendered anergic. If these destructive or inactivating mechanisms fail and self-reactive lymphocytes persist and become activated, autoimmunity may result.
Alteration of tissue antigen structure: A "self" antigen might undergo structural modification due to exposure to a chemical, drug, microorganism (e.g., viral infection), radiation, or other factors. This altered self-antigen may then be incorrectly perceived as "foreign" by the immune system, initiating an immune response against the modified self-structure.
Cross-reactive antigens (Molecular Mimicry): A foreign antigen (e.g., a microbial pathogen component) may bear a strong structural resemblance to a self-antigen. The body mounts an immune response against the foreign antigen, but the antibodies or T-cells generated are then "fooled" into reacting against the similar self-antigen, leading to autoimmune damage. A classic example is rheumatic fever following streptococcal infection.
Sequestered antigens: Certain tissues (e.g., brain, central nervous system, gonads, lens and cornea of the eye, sperm) are normally protected from immunosurveillance by immunologic barriers (e.g., blood-brain barrier) from early development. If these tissues are suddenly exposed to the immune system due to injury, trauma, or illness, their antigens may be recognized as foreign because the immune system has not developed tolerance to them, triggering an autoimmune response.
Loss of T-cell regulatory function: Regulatory T-cells (Tregs), a subset of T-lymphocytes (often CD4+CD25+FOXP3+), play a crucial role in maintaining peripheral tolerance and suppressing autoreactive immune responses. If this regulatory function is lost or impaired, it can lead to an increased and unregulated immune reaction against self-antigens, promoting autoimmune disease.