Medical School · Year 2 · Pathology · includes a quiz and discussion video

Lecture 10: Immunopathology

Unit 2.11: Pathology

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the mechanisms of hypersensitivity reactions
2. Explain the pathophysiology of autoimmune diseases
3. Describe immunodeficiency disorders
4. Explain transplant rejection mechanisms
5. Describe amyloidosis
6. Explain the pathology of common autoimmune diseases

Lecture Outline

I. Hypersensitivity Reactions Overview

Hypersensitivity reactions represent immune responses that, rather than protecting the host, cause tissue damage through exaggerated or misdirected mechanisms. These reactions are classified into four types based on the immunologic mechanism involved and the timing of the response. Type I reactions are mediated by IgE antibodies and occur within minutes of allergen exposure. Type II reactions involve IgG or IgM antibodies directed against cell surface or tissue antigens, developing over hours to days. Type III reactions result from the deposition of antigen-antibody immune complexes in tissues, also occurring over hours to days. Type IV reactions are mediated by T cells rather than antibodies and characteristically develop over days, reflecting the time required for T cell activation and effector function.

Type I hypersensitivity, also known as immediate hypersensitivity, proceeds through a well-defined sequence beginning with sensitization and culminating in mast cell degranulation upon re-exposure. During the sensitization phase, initial allergen exposure is processed by antigen-presenting cells and presented to T helper 2 (Th2) cells, which produce cytokines including IL-4 and IL-13 that drive B cell class switching to IgE production. The secreted IgE binds to high-affinity Fc epsilon receptors (FceRI) on the surface of mast cells and basophils, arming these cells for subsequent encounters with the same allergen. Upon re-exposure, the allergen cross-links adjacent IgE molecules on the mast cell surface, triggering degranulation with the explosive release of preformed mediators including histamine and tryptase. The immediate response occurs within minutes, producing vasodilation, increased vascular permeability, smooth muscle contraction, and mucus secretion. A late-phase response develops over hours as newly synthesized mediators including leukotrienes and cytokines recruit eosinophils and other inflammatory cells, producing a more sustained inflammatory reaction.

Type I hypersensitivity produces both localized and systemic clinical manifestations depending on the route and extent of allergen exposure. Local manifestations include allergic rhinitis with nasal congestion and sneezing from inhaled allergens, asthma with bronchospasm and airway inflammation, food allergy with gastrointestinal symptoms, and urticaria with localized wheal-and-flare reactions in the skin. Systemic manifestations occur when mast cell activation is widespread, as in systemic mast cell activation syndrome. The most dangerous systemic manifestation is anaphylaxis, a life-threatening condition requiring immediate treatment.

Anaphylaxis represents the most severe form of Type I hypersensitivity, in which massive, systemic mast cell degranulation produces a rapidly progressive and potentially fatal reaction. The underlying cause is IgE-mediated activation resulting in massive mediator release throughout the body simultaneously. The clinical manifestations reflect the widespread effects of histamine and other mediators: hypotension from profound vasodilation and increased vascular permeability, bronchospasm producing wheezing and respiratory distress, urticaria with generalized hives, and angioedema with swelling of the lips, tongue, and airway that may cause complete obstruction. The mechanism involves both vasodilation reducing systemic vascular resistance and increased capillary permeability allowing fluid extravasation into tissues. Epinephrine is the treatment of choice, acting as a physiologic antagonist to reverse vasodilation through alpha-adrenergic vasoconstriction, relieve bronchospasm through beta-2 agonism, and suppress further mediator release from mast cells.

<image>Panel A: Type I hypersensitivity mechanism showing initial sensitization with allergen presentation, Th2 activation, B cell IgE production, and IgE binding to mast cell Fc receptors. Panel B: Re-exposure phase with allergen cross-linking IgE on mast cells causing degranulation and release of histamine, leukotrienes, and prostaglandins with immediate vascular effects. Panel C: Comparison of immediate response (minutes, histamine-mediated vasodilation and bronchospasm) versus late phase response (hours, cytokine-mediated inflammation with eosinophil recruitment). Panel D: Anaphylaxis clinical manifestations including hypotension from vasodilation, bronchospasm with wheezing, urticaria, angioedema, and treatment with epinephrine.</image>

II. Type II and III Hypersensitivity

Type II hypersensitivity involves antibodies, typically IgG or IgM, directed against antigens present on cell surfaces or within the extracellular matrix, producing tissue damage through three distinct mechanisms. Opsonization and phagocytosis occur when antibodies coat target cells, marking them for destruction by phagocytes or complement-mediated lysis, as exemplified by autoimmune hemolytic anemia in which anti-red blood cell antibodies cause erythrocyte destruction. Complement activation by cell-bound antibodies generates the membrane attack complex and anaphylatoxins, producing direct cell lysis and inflammatory cell recruitment, as occurs in acute hemolytic transfusion reactions when ABO-incompatible blood is transfused. Antibody-mediated cellular dysfunction represents a unique mechanism in which antibodies bind to cell surface receptors and either stimulate or block their function without causing cell destruction, as seen in Graves disease where anti-TSH receptor antibodies stimulate the thyroid and in myasthenia gravis where anti-acetylcholine receptor antibodies block neuromuscular transmission.

Type II hypersensitivity underlies a diverse group of diseases, each defined by the specific target antigen against which the pathogenic antibodies are directed. Autoimmune hemolytic anemia results from antibodies targeting red blood cell surface antigens, leading to complement-mediated lysis and splenic sequestration. Goodpasture syndrome involves anti-glomerular basement membrane antibodies targeting type IV collagen, producing a linear immunofluorescence pattern and causing rapidly progressive glomerulonephritis often accompanied by pulmonary hemorrhage. Pemphigus vulgaris is caused by antibodies against desmoglein, a desmosomal adhesion protein, resulting in loss of keratinocyte cohesion and life-threatening blistering of the skin and mucous membranes. Myasthenia gravis results from antibodies that block the acetylcholine receptor (AChR) at the neuromuscular junction, producing fatigable skeletal muscle weakness. Graves disease involves stimulatory antibodies directed against the TSH receptor on thyroid follicular cells, causing unregulated thyroid hormone production and hyperthyroidism.

Type III hypersensitivity results from the formation and deposition of antigen-antibody immune complexes in tissues, where they activate complement and recruit neutrophils to produce inflammatory damage. The pathogenesis requires three elements: the formation of antigen-antibody complexes in the circulation, their deposition in vessel walls and tissue structures particularly the glomerular basement membrane, and the subsequent activation of complement with generation of chemotactic factors that recruit neutrophils whose enzymes damage the surrounding tissue. This mechanism produces vasculitis when complexes deposit in blood vessel walls and glomerulonephritis when they lodge in the glomerular capillary loops. Local immune complex reactions are exemplified by the Arthus reaction, in which intradermal injection of antigen into a previously sensitized individual produces localized vasculitis at the injection site. Systemic immune complex disease is exemplified by serum sickness, in which exposure to a large quantity of foreign antigen produces circulating complexes that deposit in multiple organs.

Type III hypersensitivity contributes to several important clinical diseases characterized by immune complex-mediated tissue damage. Systemic lupus erythematosus (SLE) represents the prototypical immune complex disease, in which DNA-anti-dsDNA complexes deposit in the kidneys, skin, joints, and serosal surfaces, producing the multi-organ manifestations that characterize this condition. Post-streptococcal glomerulonephritis results from the deposition of immune complexes containing streptococcal antigens in the glomeruli, typically occurring one to three weeks after a group A streptococcal pharyngitis or skin infection. Polyarteritis nodosa is a systemic vasculitis in which hepatitis B antigen-antibody complexes deposit in medium-sized arterial walls, producing segmental necrotizing inflammation. Serum sickness occurs following exposure to exogenous antigens, classically foreign serum proteins or certain drugs, producing fever, urticaria, arthralgia, and glomerulonephritis as circulating immune complexes deposit in multiple tissue sites.

<image>Panel A: Type II hypersensitivity mechanisms showing antibody binding to cell surface antigens causing opsonization and phagocytosis (autoimmune hemolytic anemia), complement-mediated lysis (transfusion reaction), and receptor dysfunction (Graves stimulating, myasthenia blocking). Panel B: Type II examples with target antigens including RBC membrane in hemolysis, glomerular basement membrane in Goodpasture, desmoglein in pemphigus, and TSH receptor in Graves disease. Panel C: Type III immune complex disease showing antigen-antibody complex formation, deposition in vessel walls and glomeruli, complement activation, and neutrophil recruitment causing vasculitis. Panel D: Type III clinical examples including systemic lupus erythematosus with DNA-anti-DNA complexes, poststreptococcal glomerulonephritis, and serum sickness following drug exposure.</image>

III. Type IV Hypersensitivity

Type IV hypersensitivity, also known as delayed-type hypersensitivity, is uniquely mediated by T cells rather than antibodies, and encompasses two major subtypes based on the effector T cell population involved. The delayed-type hypersensitivity subtype is mediated by CD4+ Th1 cells that release cytokines, particularly interferon-gamma, to activate macrophages and produce tissue inflammation, as exemplified by the tuberculin skin test and contact dermatitis. The cytotoxic subtype is mediated by CD8+ cytotoxic T lymphocytes that directly kill target cells expressing foreign or altered self-antigens on MHC class I molecules, as seen in viral hepatitis where cytotoxic T cells destroy virus-infected hepatocytes and in the cellular component of transplant rejection.

Delayed-type hypersensitivity proceeds through two distinct phases separated by days to weeks. The sensitization phase occurs upon initial antigen exposure, when antigen-presenting cells process and present the antigen to naive CD4+ T cells, which differentiate into Th1 memory cells over a period of days. The challenge or effector phase occurs upon subsequent exposure to the same antigen, when memory T cells recognize the antigen and mount a rapid response, releasing cytokines that recruit and activate macrophages over 24 to 72 hours. The resulting pathology is characterized by induration, a firm, raised area of tissue thickening produced by the perivascular accumulation of macrophages and T lymphocytes that infiltrate the site in response to the chemotactic signals released by activated T cells.

Contact dermatitis represents one of the most commonly encountered forms of Type IV hypersensitivity, affecting millions of individuals through exposure to environmental and occupational antigens. The mechanism is Th1-mediated, with the initial sensitization occurring when small reactive molecules called haptens penetrate the skin, bind covalently to endogenous carrier proteins, and are processed by Langerhans cells for presentation to T cells in draining lymph nodes. Classic examples include poison ivy, in which urushiol acts as the hapten, and nickel allergy, one of the most common causes of contact dermatitis worldwide. The pathology is characterized by spongiotic dermatitis, in which intercellular edema within the epidermis produces sponge-like widening of spaces between keratinocytes, often progressing to vesicle formation with the accumulation of inflammatory fluid.

Granulomatous inflammation represents a specialized form of Type IV hypersensitivity that develops when macrophages are unable to completely eliminate a persistent antigen, leading to the chronic organized accumulation of activated macrophages. Tuberculosis exemplifies this response, in which mycobacterial antigens provoke sustained Th1-mediated macrophage activation, producing the characteristic caseating granulomas that are the histologic hallmark of the disease. Sarcoidosis produces non-caseating granulomas in multiple organs, particularly the lungs, lymph nodes, and skin, driven by an immune response to an as-yet unidentified antigen. Crohn disease of the gastrointestinal tract features non-caseating granulomas as part of its transmural inflammatory pattern, again with the inciting antigen remaining unknown. Foreign body granulomas form around persistent non-degradable materials such as sutures, talc, or silicone, representing the macrophage system's attempt to wall off material it cannot digest.

<image>Panel A: Delayed-type hypersensitivity mechanism showing antigen presentation to CD4+ Th1 cells, memory T cell activation on re-exposure, IFN-gamma release, and macrophage recruitment producing induration at 24-72 hours. Panel B: Tuberculin skin test showing intradermal PPD injection, positive induration measuring greater than 10mm indicating prior TB exposure or infection, with cross-section of skin showing lymphocyte and macrophage infiltration. Panel C: Contact dermatitis from poison ivy or nickel showing hapten binding to carrier protein, T cell sensitization, and subsequent spongiotic dermatitis with vesicle formation on re-exposure. Panel D: Granulomatous inflammation showing organized macrophage aggregates in response to persistent antigens in tuberculosis, sarcoidosis, and Crohn disease with central epithelioid cells and giant cells.</image>

IV. Autoimmune Diseases - Overview

Autoimmune diseases arise from a fundamental breakdown in immunologic tolerance, the process by which the immune system normally distinguishes self from non-self and avoids attacking the body's own tissues. Multiple mechanisms have been identified that can lead to the development of autoimmunity. Molecular mimicry occurs when a pathogen expresses antigens that structurally resemble host proteins, so that the immune response directed against the pathogen cross-reacts with self-tissue, as exemplified by the relationship between streptococcal M protein and cardiac myosin in rheumatic heart disease. Epitope spreading describes the process by which tissue damage from an initial immune response exposes previously hidden self-antigens, generating new immune responses against these newly revealed epitopes and expanding the autoimmune attack. Failure of tolerance, whether central tolerance in the thymus and bone marrow or peripheral tolerance through regulatory T cells and anergy, allows autoreactive lymphocytes to survive and become activated. Polyclonal activation occurs when certain infections or substances non-specifically activate B cells, bypassing the normal requirement for T cell help and producing autoantibodies.

The development of autoimmune disease requires the convergence of multiple predisposing factors, no single one of which is sufficient alone. Genetic factors, particularly associations with specific human leukocyte antigen (HLA) alleles, represent the strongest identified risk factors, as HLA molecules determine which peptides are presented to T cells and thereby influence the repertoire of immune responses. Environmental factors, including infections that may trigger molecular mimicry or provide adjuvant signals, and drugs that may alter self-proteins or directly activate immune cells, serve as common triggers in genetically susceptible individuals. Hormonal factors account for the striking female predominance observed in most autoimmune diseases, with estrogen generally enhancing and testosterone suppressing immune responses. Defects in immunoregulation, particularly inadequate numbers or function of regulatory T cells (Tregs) that normally suppress autoreactive lymphocytes, remove a critical brake on autoimmune responses.

Autoimmune diseases are broadly classified into organ-specific and systemic categories based on the distribution of target antigens. Organ-specific autoimmune diseases direct their attack against antigens confined to a single organ, as seen in Hashimoto thyroiditis targeting the thyroid, Graves disease stimulating the thyroid through autoantibodies, and type 1 diabetes mellitus destroying pancreatic beta cells. Systemic autoimmune diseases involve immune responses against widely distributed antigens, producing multi-organ damage as exemplified by SLE, rheumatoid arthritis, and Sjogren syndrome. Overlap syndromes, such as mixed connective tissue disease, share features of multiple autoimmune conditions and may transition between categories over time.

Specific HLA associations have been identified for many autoimmune diseases, providing insight into genetic susceptibility and pathogenic mechanisms. Ankylosing spondylitis demonstrates the strongest known HLA association, with HLA-B27 present in over 90% of affected individuals compared to approximately 8% of the general population. Rheumatoid arthritis is associated with HLA-DR4, which presents citrullinated peptides that are targeted by the disease-specific anti-CCP antibodies. Type 1 diabetes mellitus shows associations with both HLA-DR3 and HLA-DR4, with the heterozygous DR3/DR4 combination conferring the highest risk. SLE is associated with HLA-DR2 and HLA-DR3, contributing to the immune dysregulation that produces the characteristic multi-organ immune complex disease. Celiac disease demonstrates a strong association with HLA-DQ2 and HLA-DQ8, which present gliadin-derived peptides that drive the destructive T cell response against the small intestinal mucosa.

<image>Panel A: Mechanisms of tolerance breakdown including molecular mimicry with cross-reactive antibodies, epitope spreading exposing new self-antigens, failure of central or peripheral tolerance, and polyclonal B cell activation. Panel B: Factors contributing to autoimmunity showing genetic susceptibility (HLA associations), environmental triggers (infections, drugs), hormonal influences (female predominance), and regulatory T cell defects. Panel C: Classification comparing organ-specific autoimmune diseases (Hashimoto thyroiditis, Graves disease, Type 1 diabetes affecting single organs) versus systemic diseases (SLE, RA, Sjogren affecting multiple organs). Panel D: Table of HLA associations with diseases including B27 and ankylosing spondylitis, DR4 and rheumatoid arthritis, DR3/DR4 and Type 1 diabetes, and DQ2/DQ8 and celiac disease.</image>

V. Specific Autoimmune Diseases

Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease, characterized by the production of autoantibodies against nuclear antigens and the deposition of immune complexes in multiple organs. The target of the immune response encompasses multiple nuclear and cytoplasmic components, producing a diverse array of autoantibodies: antinuclear antibodies (ANA) are present in virtually all SLE patients and serve as a sensitive screening test, anti-double-stranded DNA (anti-dsDNA) antibodies correlate with disease activity and are relatively specific for SLE, and anti-Smith antibodies targeting small nuclear ribonucleoproteins are highly specific though present in only a subset of patients. The pathology is driven primarily by immune complex deposition, particularly DNA-anti-dsDNA complexes that lodge in glomerular capillaries, dermal vessels, and serosal surfaces. Lupus nephritis, classified into six histologic classes (I through VI), represents the most clinically significant organ manifestation and a major determinant of prognosis. Skin involvement includes the characteristic malar (butterfly) rash over the cheeks sparing the nasolabial folds, as well as discoid lesions with scarring and photosensitivity. Libman-Sacks endocarditis produces sterile vegetations on both surfaces of the mitral valve, distinguishing it from the vegetations of infective endocarditis that occur only on the valve's atrial surface.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily targets the synovium of joints, producing progressive inflammation and destruction of articular structures. The primary target is the synovial membrane, where an intense inflammatory infiltrate of lymphocytes, macrophages, and plasma cells produces synovial hyperplasia and the formation of pannus, a mass of inflamed granulation tissue that erodes into cartilage and bone. Autoantibodies characteristic of RA include rheumatoid factor (RF), an IgM antibody directed against the Fc portion of IgG, and anti-cyclic citrullinated peptide (anti-CCP) antibodies, which are more specific for the disease and may be detected years before clinical onset. The joint involvement is characteristically symmetric, preferentially affecting the metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, and wrists, with relative sparing of the distal interphalangeal joints. Extra-articular manifestations include subcutaneous rheumatoid nodules with central fibrinoid necrosis surrounded by palisading histiocytes, interstitial lung disease, and secondary amyloidosis.

Type 1 diabetes mellitus is an autoimmune disease in which T cell-mediated destruction of pancreatic beta cells produces absolute insulin deficiency. The primary immunologic target is the beta cells within the islets of Langerhans, with the destructive process driven primarily by CD8+ cytotoxic T lymphocytes and CD4+ helper T cells that infiltrate the islets in a pattern termed insulitis. Autoantibodies, including anti-glutamic acid decarboxylase (anti-GAD) antibodies and anti-islet cell antibodies, serve as serologic markers of the autoimmune process and may be detected years before clinical onset, though the antibodies themselves are not the primary effectors of beta cell destruction. The pathologic hallmark is insulitis, the lymphocytic infiltration of pancreatic islets that progressively destroys beta cells until insulin secretory capacity is insufficient to maintain glucose homeostasis. There is a strong genetic component, with HLA-DR3 and HLA-DR4 alleles conferring the greatest susceptibility, and the DR3/DR4 heterozygous genotype carrying the highest risk of all.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system in which T cell-mediated attack on myelin produces progressive neurologic disability. The primary target is the myelin sheath surrounding axons in the brain and spinal cord, with the destructive process mediated primarily by autoreactive T cells that recognize myelin-associated antigens. The characteristic pathology consists of demyelinated plaques, sharply demarcated areas of myelin loss with relative preservation of axons, distributed throughout the white matter with a predilection for periventricular regions, the optic nerves, brainstem, and spinal cord. Cerebrospinal fluid analysis reveals oligoclonal bands, representing intrathecal immunoglobulin synthesis by clonally expanded B cells within the central nervous system, which serve as a diagnostic marker for the disease.

<image>Panel A: Systemic lupus erythematosus showing malar butterfly rash sparing nasolabial folds, lupus nephritis with wire-loop deposits on histology and immunofluorescence showing granular immune complex deposition, and Libman-Sacks endocarditis vegetations on both valve surfaces. Panel B: Rheumatoid arthritis demonstrating symmetric joint involvement of MCP and PIP joints, pannus tissue eroding cartilage and bone, subcutaneous rheumatoid nodule with central fibrinoid necrosis surrounded by palisading histiocytes. Panel C: Type 1 diabetes mellitus showing insulitis with lymphocytic infiltration of pancreatic islets, beta cell destruction, and autoantibodies against GAD65 and islet cell antigens. Panel D: Multiple sclerosis with periventricular white matter plaques on MRI, demyelination preserving axons on histology, and oligoclonal bands in cerebrospinal fluid.</image>

VI. Primary Immunodeficiencies

Primary immunodeficiencies are inherited disorders of the immune system that are classified according to which component of immune defense is deficient. B cell deficiencies produce impaired antibody production, leading to susceptibility to infections with extracellular organisms, particularly encapsulated bacteria. T cell deficiencies impair cell-mediated immunity, predisposing to infections with intracellular pathogens including viruses, fungi, and mycobacteria. Combined immunodeficiencies affect both B and T cell function, producing the most severe susceptibility to all classes of pathogens. Phagocyte deficiencies impair the ability of neutrophils and macrophages to ingest and kill pathogens, creating vulnerability to bacterial and fungal infections. Complement deficiencies affect specific components of the complement cascade, producing susceptibility patterns that depend on which component is missing.

B cell deficiencies present with recurrent bacterial infections, particularly of the respiratory and gastrointestinal tracts, due to the inability to produce protective antibodies. X-linked agammaglobulinemia (Bruton disease) results from a mutation in the Bruton tyrosine kinase (BTK) gene, which is essential for B cell maturation, causing a complete arrest at the pre-B cell stage with absent mature B cells and all immunoglobulin classes in the serum. Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by low levels of immunoglobulins with variable clinical presentation that may include recurrent sinopulmonary infections, autoimmune cytopenias, and increased risk of lymphoma. Selective IgA deficiency is the most common primary immunodeficiency overall, affecting approximately 1 in 600 individuals, and is often asymptomatic, though some patients experience recurrent mucosal infections and are at risk for anaphylaxis if transfused with IgA-containing blood products. The infections characteristic of antibody deficiencies are those caused by encapsulated bacteria, particularly Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus, which require opsonizing antibodies for efficient clearance.

T cell deficiencies and combined immunodeficiencies produce devastating susceptibility to a broad range of pathogens, reflecting the central role of T cells in coordinating immune responses. DiGeorge syndrome results from a deletion at chromosome 22q11, producing defective development of the third and fourth pharyngeal pouches and consequently thymic aplasia or hypoplasia with absent or severely reduced T cell numbers. Severe combined immunodeficiency (SCID) represents the most severe form of primary immunodeficiency, with multiple genetic causes including IL-2 receptor gamma chain mutations (X-linked), adenosine deaminase deficiency, and RAG1/RAG2 mutations, all producing profound deficiency of both T and B cell function that is uniformly fatal without bone marrow transplantation or gene therapy. Wiskott-Aldrich syndrome is an X-linked disorder characterized by the clinical triad of eczema, thrombocytopenia with small platelets, and recurrent infections, resulting from mutations in the WASP gene that affects cytoskeletal organization in hematopoietic cells. Infections in patients with T cell deficiency characteristically involve intracellular pathogens and opportunistic organisms, including mycobacteria, fungi, Pneumocystis, and herpesviruses.

Phagocyte deficiencies impair the ability to ingest and kill pathogens, particularly catalase-positive bacteria and fungi. Chronic granulomatous disease (CGD) results from mutations in components of the NADPH oxidase complex, preventing the generation of the respiratory burst that is essential for intracellular killing of phagocytosed organisms. Patients with CGD are characteristically susceptible to catalase-positive organisms, including Staphylococcus aureus, Aspergillus, and Nocardia, because catalase-positive organisms destroy their own hydrogen peroxide, removing the alternative killing mechanism that normally compensates for the absent respiratory burst. The inability to completely clear these organisms leads to chronic granuloma formation, giving the disease its name. Leukocyte adhesion deficiency results from defective integrins on leukocyte surfaces, preventing neutrophils from adhering to endothelium and migrating to sites of infection, producing the paradoxical finding of high circulating neutrophil counts but absent pus formation at infection sites. Chediak-Higashi syndrome is characterized by giant cytoplasmic granules in neutrophils and other cells resulting from defective granule fusion, producing impaired microbicidal activity along with partial oculocutaneous albinism. Infections in patients with phagocyte deficiencies are predominantly caused by bacteria and fungi that require phagocytic killing for clearance.

<image>Panel A: X-linked agammaglobulinemia showing BTK gene mutation causing arrest at pre-B cell stage, absent mature B cells and immunoglobulins, absent lymph node germinal centers, and recurrent sinopulmonary infections with encapsulated bacteria. Panel B: Severe combined immunodeficiency (SCID) with absent T and B cell function, thymic hypoplasia, susceptibility to all pathogen types including opportunistic organisms, and need for bone marrow transplant. Panel C: Chronic granulomatous disease showing NADPH oxidase deficiency preventing respiratory burst, inability to kill catalase-positive organisms (Staph aureus, Aspergillus, Nocardia), and granuloma formation from incomplete pathogen clearance. Panel D: DiGeorge syndrome with 22q11 deletion causing thymic aplasia, T cell deficiency, characteristic facies, cardiac defects, and hypocalcemia from parathyroid hypoplasia.</image>

VII. Secondary Immunodeficiencies

Secondary immunodeficiencies are acquired conditions in which immune function is compromised by external factors rather than inherited genetic defects, and collectively they are far more common than primary immunodeficiencies. The causes are diverse and encompass multiple categories. Infections, most notably HIV/AIDS, directly destroy immune cells and produce profound immunosuppression. Medications including chemotherapeutic agents, corticosteroids, and immunosuppressive drugs used for transplantation and autoimmune diseases deliberately or inadvertently impair immune function. Malignancies, particularly lymphomas and leukemias, disrupt normal immune cell production and function through replacement of bone marrow and lymphoid tissues. Malnutrition, especially protein-calorie malnutrition, impairs virtually all aspects of immune function and is the most common cause of immunodeficiency worldwide. Metabolic conditions such as diabetes mellitus with its impaired neutrophil function and uremia with its broad immunosuppressive effects contribute to infection susceptibility. Splenectomy, whether surgical or functional, removes the critical splenic filter and its role in clearing encapsulated organisms from the bloodstream.

HIV/AIDS represents the most clinically significant secondary immunodeficiency, progressing through well-defined stages that correlate with the CD4+ T cell count. The acute stage is characterized by a high viral load with explosive viral replication, producing a flu-like syndrome with fever, lymphadenopathy, and rash in approximately 50 to 70 percent of patients, often occurring two to four weeks after exposure. The chronic or latent stage is characterized by gradual decline of CD4+ T cells over years, during which the patient may remain largely asymptomatic while ongoing viral replication slowly erodes the immune system. AIDS develops when the CD4 count falls below 200 cells per microliter or when an AIDS-defining condition occurs, marking the onset of profound immunodeficiency with susceptibility to opportunistic infections and malignancies.

AIDS-defining conditions encompass a specific set of opportunistic infections and malignancies that rarely occur in immunocompetent individuals and signal the transition to advanced HIV disease. The infections include Pneumocystis jirovecii pneumonia (PCP), the most common AIDS-defining illness, along with cytomegalovirus disease, Mycobacterium avium complex (MAC) disseminated infection, and Toxoplasma gondii encephalitis with its characteristic ring-enhancing brain lesions. The malignancies include Kaposi sarcoma caused by human herpesvirus 8 (HHV-8), non-Hodgkin lymphoma (particularly primary central nervous system lymphoma associated with EBV), and invasive cervical carcinoma associated with HPV. Other AIDS-defining conditions include HIV wasting syndrome with significant involuntary weight loss and HIV-associated dementia reflecting direct viral effects on the central nervous system.

Iatrogenic immunosuppression has become increasingly common as transplantation, autoimmune disease treatment, and cancer therapy require deliberate suppression of immune function. Post-transplant patients on chronic immunosuppression are particularly susceptible to CMV reactivation, EBV-associated post-transplant lymphoproliferative disorder, and invasive Aspergillus infection, with the specific risk depending on the intensity and type of immunosuppressive regimen. Chemotherapy-induced neutropenia creates a window of vulnerability during which patients are susceptible to severe bacterial and fungal infections until neutrophil counts recover. TNF inhibitors, widely used for rheumatoid arthritis, inflammatory bowel disease, and other autoimmune conditions, carry a specific risk of tuberculosis reactivation, mandating TB screening before initiation of therapy. Rituximab, an anti-CD20 monoclonal antibody that depletes B cells, carries a risk of hepatitis B virus reactivation in patients with prior exposure, necessitating HBV screening and prophylaxis.

<image>Panel A: HIV disease progression showing acute phase with high viral load and flu-like symptoms, chronic phase with gradual CD4 decline, and AIDS when CD4 drops below 200 with opportunistic infections. Panel B: AIDS-defining opportunistic infections including Pneumocystis jirovecii pneumonia with bilateral interstitial infiltrates, CMV retinitis with hemorrhages and exudates, cerebral toxoplasmosis with ring-enhancing lesions, and Mycobacterium avium complex. Panel C: AIDS-associated malignancies showing Kaposi sarcoma purple skin lesions with spindle cells and vascular slits, primary CNS lymphoma, and invasive cervical carcinoma. Panel D: Iatrogenic immunosuppression showing post-transplant infections (CMV, EBV, Aspergillus), chemotherapy-induced neutropenia susceptibility, and TNF inhibitor-associated tuberculosis reactivation.</image>

VIII. Transplant Rejection

Transplant rejection occurs when the recipient's immune system recognizes donor tissue as foreign and mounts a destructive immune response, classified into three types based on timing and mechanism. Hyperacute rejection occurs within minutes of transplantation and is mediated by preformed antibodies in the recipient's serum. Acute rejection develops over weeks to months and involves both T cell-mediated and antibody-mediated mechanisms. Chronic rejection evolves over months to years through a combination of immune and non-immune mechanisms that produce progressive fibrosis and graft dysfunction. Understanding these distinct mechanisms is essential for prevention through proper donor-recipient matching and for treatment when rejection occurs.

Hyperacute rejection is the most rapid and dramatic form, occurring within minutes to hours of establishing blood flow to the transplanted organ. The mechanism involves preformed anti-donor antibodies, typically directed against ABO blood group antigens or donor HLA molecules, that are already present in the recipient's circulation at the time of transplantation. These antibodies immediately bind to the vascular endothelium of the graft, activating complement and the coagulation cascade. The pathology is characterized by widespread thrombosis within graft vessels, hemorrhagic necrosis of the transplanted organ, and rapid graft failure. Prevention is achieved through pre-transplant crossmatching, in which recipient serum is tested against donor cells to detect preformed antibodies, and ABO compatibility testing. Hyperacute rejection has become rare in modern transplantation due to these routine screening procedures.

Acute rejection is the most common form of clinically significant rejection and occurs through two distinct but often overlapping mechanisms. Acute cellular rejection is mediated by CD8+ cytotoxic T lymphocytes that recognize donor HLA molecules either directly on the surface of graft cells or indirectly through processing and presentation by recipient antigen-presenting cells. The pathology is characterized by lymphocytic infiltration of the graft parenchyma with endotheliitis, in which lymphocytes attach to and damage the endothelium of graft blood vessels. Acute humoral (antibody-mediated) rejection is mediated by anti-HLA antibodies produced by the recipient against donor antigens, with complement activation producing vascular damage detectable by C4d deposition in peritubular capillaries on immunofluorescence staining. Treatment of acute rejection depends on the mechanism: cellular rejection typically responds to high-dose corticosteroids or anti-thymocyte globulin (ATG), while humoral rejection requires plasmapheresis to remove circulating antibodies.

Chronic rejection represents the most difficult form of rejection to treat and is the leading cause of long-term graft loss. It develops over months to years through a combination of immune-mediated injury, including repeated subclinical episodes of acute rejection, and non-immune factors such as calcineurin inhibitor toxicity and chronic ischemia. The pathology is characterized by progressive vascular intimal thickening with concentric fibrosis that narrows the lumen of graft blood vessels, producing ischemia and gradual parenchymal atrophy. Interstitial fibrosis and tubular atrophy in kidney transplants, bronchiolitis obliterans in lung transplants, and accelerated coronary atherosclerosis in heart transplants represent organ-specific manifestations of this process. The outcome is progressive and generally irreversible graft dysfunction leading to eventual graft loss, emphasizing the importance of adherence to immunosuppressive therapy to prevent the repeated immune injuries that drive chronic rejection.

<image>Panel A: Hyperacute rejection occurring within minutes from preformed anti-donor antibodies binding vascular endothelium, complement activation causing thrombosis, hemorrhage, and graft necrosis, prevented by pre-transplant crossmatching. Panel B: Acute cellular rejection showing CD8+ T cell infiltration of graft parenchyma, tubulitis in kidney transplants with lymphocytes invading tubular epithelium, and endotheliitis with lymphocyte attachment to vessel walls. Panel C: Acute humoral rejection with C4d deposition in peritubular capillaries detected by immunofluorescence, donor-specific anti-HLA antibodies, and treatment with plasmapheresis. Panel D: Chronic rejection developing over months to years showing progressive vascular intimal thickening with concentric fibrosis, interstitial fibrosis with tubular atrophy, and irreversible graft dysfunction.</image>

IX. Graft-vs-Host Disease

Graft-versus-host disease (GVHD) represents a unique form of immune-mediated tissue damage in which immunocompetent donor cells attack the tissues of an immunocompromised recipient, essentially reversing the usual direction of transplant rejection. The setting is almost exclusively bone marrow or hematopoietic stem cell transplantation, where the graft inherently contains mature donor T lymphocytes along with the desired stem cells. The mechanism involves donor T cells that recognize host tissues as foreign due to HLA disparity, becoming activated and mounting a destructive immune response against recipient epithelial tissues. The requirements for GVHD to develop include the presence of immunocompetent cells within the graft, an HLA mismatch between donor and recipient sufficient to drive immune recognition, and a host who is immunocompromised and unable to reject the donor cells.

Acute GVHD classically develops within the first 100 days following transplantation and targets three principal organ systems. The skin is the most commonly affected organ, producing a maculopapular rash that often begins on the palms and soles before becoming generalized, and may progress to bullous disease with extensive epidermal necrosis in severe cases. The liver is involved through bile duct destruction by donor T cells, producing elevated bilirubin and cholestatic liver injury. The gastrointestinal tract develops mucosal inflammation with crypt cell necrosis, manifesting as profuse watery diarrhea, nausea, vomiting, and abdominal pain. The combination of skin rash, jaundice, and diarrhea in a recent transplant recipient should immediately raise suspicion for acute GVHD.

Chronic GVHD develops beyond 100 days post-transplant and is characterized by a clinical presentation that closely resembles various autoimmune diseases, reflecting the ongoing immune dysregulation produced by donor T cells. Skin involvement produces scleroderma-like changes with progressive dermal fibrosis, tightening, and contractures that may severely limit mobility. Mucosal involvement produces a sicca syndrome resembling Sjogren syndrome, with dry eyes and dry mouth from destruction of lacrimal and salivary glands. Pulmonary involvement manifests as bronchiolitis obliterans, an obstructive airway disease caused by fibrotic narrowing and obliteration of small airways, producing progressive dyspnea and irreversible airflow limitation. Other manifestations may include fasciitis, esophageal stricture, and chronic liver disease.

Prevention and treatment of GVHD employ several complementary strategies aimed at reducing the donor T cell response against host tissues. T cell depletion of the graft, either ex vivo using antibody-based methods or in vivo using anti-thymocyte globulin, reduces the number of donor T cells capable of recognizing host antigens, though aggressive depletion may increase the risk of graft failure and infection. Immunosuppressive therapy with calcineurin inhibitors such as cyclosporine or tacrolimus, often combined with corticosteroids, forms the backbone of GVHD prophylaxis by suppressing T cell activation and cytokine production. Improved HLA matching between donor and recipient reduces the degree of antigenic disparity and consequently the intensity of the donor immune response, representing the most fundamental strategy for reducing GVHD risk.

<image>Panel A: Graft-versus-host disease mechanism showing donor T cells recognizing host HLA antigens as foreign, activation and proliferation, and attack on host epithelial tissues in immunocompromised recipient after bone marrow transplant. Panel B: Acute GVHD manifesting before 100 days with maculopapular skin rash often starting on palms and soles, hepatic involvement with elevated bilirubin, and gastrointestinal disease with watery diarrhea and mucosal sloughing. Panel C: Chronic GVHD after 100 days resembling autoimmune diseases with scleroderma-like skin thickening and fibrosis, sicca syndrome affecting eyes and mouth, and bronchiolitis obliterans with progressive airflow obstruction. Panel D: GVHD skin histopathology showing apoptotic keratinocytes (satellite cell necrosis), lymphocytic infiltration at dermal-epidermal junction, and interface dermatitis pattern.</image>

X. Amyloidosis

Amyloidosis encompasses a group of diseases characterized by the extracellular deposition of abnormal fibrillar proteins that share a common structural feature: the beta-pleated sheet configuration. This misfolded protein structure renders amyloid resistant to normal proteolytic degradation, allowing it to accumulate progressively in tissues and disrupt organ function. The definitive diagnostic stain for amyloid is Congo red, which binds to the beta-pleated sheet and produces a characteristic salmon-pink color under conventional light microscopy that transforms to a pathognomonic apple-green birefringence when viewed under polarized light. Multiple different proteins can form amyloid, with each producing a distinct clinical syndrome based on the precursor protein, the pattern of organ involvement, and the underlying disease process.

Amyloidosis is classified according to the specific precursor protein that forms the amyloid fibrils, with each type associated with distinct clinical settings and organ involvement patterns. AL (amyloid light chain) amyloidosis results from the deposition of immunoglobulin light chains, typically produced by a clonal proliferation of plasma cells as seen in plasma cell dyscrasias and multiple myeloma. AA (amyloid-associated) amyloidosis results from the deposition of serum amyloid A protein, an acute-phase reactant produced in excess during states of chronic inflammation. ATTR (transthyretin) amyloidosis involves the deposition of misfolded transthyretin protein, occurring in both hereditary forms with mutant transthyretin and senile cardiac amyloidosis with wild-type transthyretin deposition in elderly patients. Abeta-2-microglobulin (Abeta2M) amyloidosis results from the accumulation of beta-2-microglobulin in patients on long-term dialysis, as this small protein is poorly cleared by conventional dialysis membranes. Amyloid-beta (Abeta) deposition in the brain forms the neuritic plaques that are a hallmark of Alzheimer disease.

AL amyloidosis is the most clinically significant form in developed countries, with organ involvement that reflects the systemic distribution of light chain deposition. The source of the pathogenic light chains is a clonal population of plasma cells, which may represent overt multiple myeloma or a more indolent plasma cell dyscrasia. The heart is a major target, with amyloid deposition in the myocardial interstitium producing a restrictive cardiomyopathy characterized by a stiff, noncompliant ventricle with diastolic dysfunction and preserved systolic function. The kidneys are commonly affected, with glomerular amyloid deposition producing heavy proteinuria and nephrotic syndrome. The tongue may enlarge dramatically, producing macroglossia that is virtually pathognomonic for AL amyloidosis. Peripheral nerves are affected, producing a progressive sensorimotor polyneuropathy.

AA amyloidosis develops as a consequence of chronic inflammatory conditions that produce sustained elevations of serum amyloid A, an acute-phase reactant synthesized by the liver. The precursor protein, serum amyloid A, circulates at elevated levels during any prolonged inflammatory state, providing the substrate for amyloid fibril formation. The most common underlying causes include rheumatoid arthritis, inflammatory bowel disease, and chronic infections such as tuberculosis and osteomyelitis, all of which maintain chronically elevated acute-phase reactants. The organs most commonly affected are the kidneys, where glomerular amyloid deposition produces progressive renal insufficiency and nephrotic syndrome, the liver with hepatomegaly and eventually hepatic dysfunction, and the spleen with characteristic patterns of involvement. The prognosis depends critically on control of the underlying inflammatory condition, as reducing serum amyloid A levels can halt and sometimes partially reverse amyloid deposition.

<image>Panel A: Amyloid detection showing Congo red staining with salmon-pink color under light microscopy and characteristic apple-green birefringence under polarized light confirming beta-pleated sheet structure. Panel B: AL amyloidosis from plasma cell dyscrasia with immunoglobulin light chain deposition in heart causing restrictive cardiomyopathy with thickened walls, kidney causing nephrotic syndrome, and tongue causing macroglossia. Panel C: AA amyloidosis from chronic inflammatory conditions (RA, IBD, chronic infections) with serum amyloid A deposition primarily affecting kidney, liver, and spleen. Panel D: Organ-specific amyloid patterns showing ATTR cardiac amyloidosis in elderly (senile) or hereditary forms, dialysis-associated beta-2-microglobulin amyloidosis in carpal tunnel, and amyloid-beta in Alzheimer disease brain plaques.</image>

Summary

• Type I: IgE-mediated; anaphylaxis, allergic rhinitis, asthma
• Type II: Antibody-mediated; hemolysis, Goodpasture, Graves
• Type III: Immune complex; SLE nephritis, serum sickness
• Type IV: T cell-mediated; TB test, contact dermatitis, granulomas
• Autoimmunity: genetic (HLA) + environmental + loss of tolerance
• SLE: multi-organ; anti-dsDNA; immune complex deposition
• Primary immunodeficiencies: B cell, T cell, combined, phagocyte
• HIV/AIDS: CD4 depletion; opportunistic infections at <200
• Transplant rejection: hyperacute (antibodies), acute (T cells), chronic (fibrosis)
• Amyloidosis: AL (light chains), AA (inflammation), ATTR (transthyretin)

Key Terms

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