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

Lecture 6: Immunodeficiency Disorders

Unit 2.7: Immunology

Learning Objectives

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

1. Describe the classification of primary immunodeficiencies
2. Explain B cell and antibody deficiency disorders
3. Describe T cell and combined immunodeficiencies
4. Explain phagocyte and complement disorders
5. Describe the clinical presentation and evaluation of immunodeficiency
6. Explain acquired immunodeficiency (HIV/AIDS)

Lecture Outline

I. Overview of Immunodeficiency

Immunodeficiency disorders encompass a diverse group of conditions characterized by defects in one or more components of the immune system, resulting in increased susceptibility to infections and, in some cases, autoimmunity and malignancy. These disorders are broadly classified as primary (congenital) immunodeficiencies, which result from genetic defects and are typically present from birth, and secondary (acquired) immunodeficiencies, which develop due to external factors such as infection, malnutrition, or immunosuppressive therapies. Understanding immunodeficiency is essential for clinicians because these conditions are underdiagnosed, treatable, and failure to recognize them leads to preventable morbidity and mortality.

The clinical presentation of immunodeficiency varies depending on which component of the immune system is affected, providing valuable diagnostic clues through pattern recognition. Patients with antibody or B cell deficiencies typically present with recurrent sinopulmonary infections caused by encapsulated bacteria, reflecting the importance of antibodies for opsonization and complement activation against these organisms. T cell and combined immunodeficiencies predispose to opportunistic infections with intracellular bacteria, viruses, fungi, and protozoa that are normally controlled by cell-mediated immunity. Phagocyte disorders manifest with deep-seated bacterial and fungal infections, particularly of skin, lymph nodes, and lungs, often with abscess formation. Complement deficiencies cause susceptibility to Neisseria infections and, for classical pathway components, autoimmune disease resembling systemic lupus erythematosus.

Warning signs that should prompt evaluation for immunodeficiency have been established to help clinicians identify affected patients. In children, these include four or more ear infections in a year, two or more serious sinus infections or pneumonias in a year, failure to thrive, need for intravenous antibiotics to clear infections, persistent thrush or skin infections, and family history of immunodeficiency. In adults, similar patterns of recurrent infections, deep-seated or unusual infections, and recurrent infections that require prolonged antibiotic courses should raise suspicion. The primary immunodeficiencies are relatively rare individually, with an overall estimated prevalence of 1:2,000 to 1:10,000 depending on the population and definition used, but collectively they represent a significant cause of morbidity. Antibody deficiencies are the most common category, while severe combined immunodeficiency, though rare (approximately 1:50,000), represents a medical emergency requiring urgent diagnosis and treatment.

The approach to evaluating suspected immunodeficiency involves systematic assessment based on the clinical pattern of infections. Initial screening tests include complete blood count with differential to identify lymphopenia or neutropenia, quantitative immunoglobulins (IgG, IgA, IgM) to detect antibody deficiencies, and HIV testing in appropriate clinical contexts. Further evaluation depends on findings and clinical suspicion, and may include lymphocyte subset analysis by flow cytometry, specific antibody responses to vaccines, complement studies (CH50, AH50), neutrophil oxidative burst testing, and ultimately genetic testing for specific diagnoses. Early diagnosis is crucial because many immunodeficiencies are treatable with immunoglobulin replacement, antimicrobial prophylaxis, or definitive correction through hematopoietic stem cell transplantation or gene therapy.

<image> Panel A: Classification diagram showing primary immunodeficiencies organized by affected component (B cell/antibody defects, T cell defects, combined B and T cell defects, phagocyte defects, complement defects) with representative examples in each category and their relative frequencies Panel B: Pattern recognition guide showing the relationship between immune component affected and typical infection patterns: antibody defects with encapsulated bacteria (Streptococcus, Haemophilus), T cell defects with opportunistic pathogens (PCP, CMV, Candida), phagocyte defects with catalase-positive organisms (Staph, Aspergillus), and complement defects with Neisseria Panel C: Warning signs infographic showing clinical indicators for immunodeficiency evaluation in children (recurrent otitis, failure to thrive, persistent thrush, family history) and adults (recurrent sinopulmonary infections, unusual pathogens, infections requiring IV antibiotics) Panel D: Diagnostic algorithm flowchart showing initial evaluation (CBC, immunoglobulins, HIV) followed by directed testing based on suspected defect (lymphocyte subsets, vaccine responses, complement studies, oxidative burst, genetic testing), with appropriate clinical pathways indicated </image>

II. B Cell and Antibody Deficiencies

B cell and antibody deficiencies comprise the largest category of primary immunodeficiencies, accounting for approximately 50% of cases, and range in severity from asymptomatic to life-threatening. These disorders impair humoral immunity, resulting in defective antibody production and susceptibility to infections with extracellular encapsulated bacteria that require opsonization for effective clearance. The clinical hallmark is recurrent sinopulmonary infections beginning after maternal antibody wanes (typically around six months of age), with progressive lung damage and bronchiectasis if untreated. Recognition and treatment with immunoglobulin replacement can prevent infectious complications and preserve lung function.

X-linked agammaglobulinemia (XLA), also known as Bruton's agammaglobulinemia, results from mutations in the BTK gene encoding Bruton's tyrosine kinase, an essential signaling molecule for B cell development. BTK is required for signaling through the pre-B cell receptor, and its absence causes developmental arrest at the pro-B to pre-B cell transition, resulting in virtual absence of mature B cells in the peripheral blood and profoundly low immunoglobulin levels of all classes. Affected males are typically healthy for the first six months of life while protected by maternal IgG, then develop recurrent bacterial infections including otitis media, sinusitis, and pneumonia. Physical examination often reveals absence of tonsils and lymph nodes due to lack of B cells populating these tissues. Diagnosis is confirmed by demonstrating absent B cells on flow cytometry and mutations in BTK, and treatment consists of lifelong immunoglobulin replacement therapy, which dramatically improves outcomes when initiated early.

Common variable immunodeficiency (CVID) is the most frequently diagnosed symptomatic primary immunodeficiency in adults, characterized by low IgG plus low IgA and/or IgM with impaired vaccine responses but presence of B cells. Unlike XLA, the genetic basis is heterogeneous and not identified in most patients, though mutations in genes involved in B cell signaling and survival (ICOS, TACI, BAFFR, CD19, CD20) have been found in subsets. CVID typically presents in the second or third decade of life with recurrent sinopulmonary infections, although onset can range from childhood to late adulthood. Beyond infections, CVID is associated with significant non-infectious complications including autoimmunity (especially autoimmune cytopenias), granulomatous disease affecting lungs and other organs, gastrointestinal disease including inflammatory bowel disease-like illness and nodular lymphoid hyperplasia, and increased risk of lymphoma. Management includes immunoglobulin replacement and treatment of specific complications.

Selective IgA deficiency is the most common primary immunodeficiency, affecting approximately 1 in 500 individuals of European descent, defined as serum IgA less than 7 mg/dL with normal IgG and IgM in individuals over four years of age. Most affected individuals are asymptomatic and diagnosed incidentally, though some experience increased respiratory and gastrointestinal infections. IgA deficiency is associated with other conditions including celiac disease, autoimmune diseases, and atopy. An important clinical consideration is that some IgA-deficient individuals develop anti-IgA antibodies that can cause anaphylactic reactions to blood products containing IgA; therefore, when transfusion is required, IgA-deficient blood products or washed cellular products should be used. Hyper-IgM syndromes represent a distinct category where class-switch recombination is impaired, resulting in normal or elevated IgM but markedly decreased IgG, IgA, and IgE. The most common form, X-linked hyper-IgM syndrome, results from CD40 ligand deficiency, which also impairs T cell-macrophage interactions and causes susceptibility to opportunistic infections including Pneumocystis and Cryptosporidium.

<image> Panel A: X-linked agammaglobulinemia pathogenesis showing BTK gene location on X chromosome, BTK protein function in pre-BCR signaling, developmental block at pro-B to pre-B transition, resulting absence of mature B cells and all immunoglobulin classes, with characteristic clinical features (absent tonsils, recurrent sinopulmonary infections after 6 months) Panel B: Common variable immunodeficiency complexity diagram showing heterogeneous genetic causes (ICOS, TACI, BAFFR, CD19 mutations in subsets), B cells present but dysfunctional, typical adult onset presentation, and the spectrum of infectious and non-infectious complications (infections, autoimmunity, granulomatous disease, GI disease, lymphoma risk) Panel C: Selective IgA deficiency showing isolated IgA absence with preserved IgG and IgM, the spectrum from asymptomatic to recurrent infections, associated conditions (celiac disease, autoimmunity), and the clinical concern regarding anti-IgA antibodies and transfusion reactions Panel D: Hyper-IgM syndrome types comparison showing Type 1 (CD40L deficiency, X-linked, opportunistic infections due to impaired T cell-macrophage interaction), Type 2 (AID deficiency, autosomal recessive, affecting only B cell class switch), with resulting immunoglobulin profiles and infection susceptibility patterns </image>

III. Transient and Specific Antibody Deficiencies

Transient hypogammaglobulinemia of infancy represents a physiological phenomenon that becomes clinically significant in some infants, characterized by delayed onset of immunoglobulin production that results in a prolonged period of hypogammaglobulinemia beyond the normal physiological nadir. During fetal life and early infancy, maternal IgG transferred across the placenta provides protection, but this passively acquired antibody has a half-life of approximately three weeks and wanes during the first six months of life. Normally, infant immunoglobulin production increases during this period, but in transient hypogammaglobulinemia, this maturation is delayed, creating a vulnerability period until the infant's own antibody production catches up, typically by two to four years of age.

The pathophysiology of transient hypogammaglobulinemia of infancy is incompletely understood but is thought to involve delayed maturation of T cell help to B cells or intrinsic delays in B cell differentiation. Unlike permanent antibody deficiencies, affected infants have normal B cell numbers and can eventually make specific antibody responses, though these may be delayed. Most infants with transient hypogammaglobulinemia are asymptomatic or have only mildly increased infections, and observation with close monitoring is appropriate. In more severe cases with significant infections, short-term immunoglobulin replacement may be considered, with periodic reassessment to document eventual normalization of immunoglobulin levels and vaccine responses. Distinguishing transient hypogammaglobulinemia from permanent conditions like CVID can be challenging initially, requiring longitudinal follow-up to demonstrate resolution.

Specific antibody deficiency (SAD) refers to inability to mount protective antibody responses to polysaccharide antigens despite normal quantitative immunoglobulin levels and normal responses to protein antigens. This condition reflects the T cell-independent nature of anti-polysaccharide responses, which require marginal zone B cells and complement and do not benefit from T cell help. Children under two years of age cannot respond to pure polysaccharide vaccines (such as the 23-valent pneumococcal polysaccharide vaccine) due to developmental immaturity of this response, but older children and adults with SAD have a persistent defect. Diagnosis requires demonstrating failure to respond to polysaccharide vaccine challenge, and clinical significance correlates with actual infection history rather than laboratory findings alone.

IgG subclass deficiency, defined as selective reduction of one or more IgG subclasses (IgG1-4) with normal total IgG, is a controversial entity of uncertain clinical significance. IgG2 deficiency has received particular attention because IgG2 antibodies predominate in responses to polysaccharide antigens, and IgG2 deficiency often coexists with IgA deficiency. However, many individuals with isolated IgG subclass deficiency are asymptomatic, and treatment decisions should be based on clinical infection history and documented functional antibody deficiency rather than subclass levels alone. Evaluation of antibody deficiency should include measurement of quantitative immunoglobulins, IgG subclasses when clinically indicated, and most importantly, functional assessment through measurement of specific antibodies before and after vaccination with both protein and polysaccharide vaccines.

<image> Panel A: Transient hypogammaglobulinemia of infancy timeline showing maternal IgG transfer during pregnancy, postnatal decline of maternal IgG with normal nadir at 3-6 months, delayed infant Ig production creating prolonged vulnerability, and eventual normalization by age 2-4 years, with comparison to normal development and to permanent immunodeficiency Panel B: Specific antibody deficiency concept showing normal total IgG and protein antigen responses (T-dependent) but absent polysaccharide responses (T-independent), the marginal zone B cell pathway for polysaccharide responses, and clinical presentation with recurrent encapsulated bacterial infections despite normal routine antibody levels Panel C: IgG subclass functions diagram showing IgG1 (anti-protein, most abundant), IgG2 (anti-polysaccharide), IgG3 (complement activation), and IgG4 (allergen tolerance), with discussion of the controversy regarding clinical significance of isolated subclass deficiency Panel D: Antibody deficiency evaluation algorithm showing stepwise approach: quantitative Ig levels, then functional assessment with pre- and post-vaccination titers using both protein (tetanus, diphtheria) and polysaccharide (Pneumovax) antigens, with interpretation guidelines and decision points for treatment </image>

IV. T Cell Immunodeficiencies

T cell immunodeficiencies range from severe combined immunodeficiency with essentially no T cell function to partial defects with variable clinical manifestations, and because T cells are required for most B cell responses, T cell defects often result in combined immunodeficiency affecting both cellular and humoral immunity. The clinical hallmark of T cell deficiency is susceptibility to opportunistic infections with organisms normally controlled by cell-mediated immunity, including Pneumocystis jirovecii, cytomegalovirus, Candida, Cryptococcus, and mycobacteria. T cell defects also impair responses to live vaccines, which can cause disseminated infection, making live vaccine avoidance critical until T cell function is established.

Severe combined immunodeficiency (SCID) represents the most severe form of primary immunodeficiency, characterized by profound defects in T cell development that also impair B cell function due to lack of T cell help. SCID is fatal in the first one to two years of life without definitive treatment, as affected infants develop overwhelming infections with opportunistic pathogens. Multiple genetic defects can cause SCID, categorized by the presence or absence of B and NK cells alongside absent T cells. X-linked SCID, the most common form, results from mutations in the common gamma chain (IL2RG) shared by receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, producing T-B+NK- SCID because IL-7 signaling is required for T cell development and IL-15 for NK cell development while B cells develop but are nonfunctional without T cell help. Adenosine deaminase (ADA) deficiency causes T-B-NK- SCID through accumulation of toxic purine metabolites that kill all lymphocyte lineages.

DiGeorge syndrome, caused by 22q11.2 deletion encompassing the TBX1 transcription factor, represents a developmental defect affecting multiple structures derived from the third and fourth pharyngeal pouches, including the thymus. The clinical syndrome, memorized as CATCH-22 (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia from parathyroid hypoplasia), varies in severity. The immunodeficiency ranges from complete DiGeorge syndrome with absent thymus and profound T cell deficiency (rare) to partial DiGeorge with thymic hypoplasia and modest T cell reduction (more common). Most patients with partial DiGeorge have mild immunodeficiency that improves with age, while complete DiGeorge requires thymus transplantation or hematopoietic stem cell transplantation for survival.

Newborn screening for SCID, now implemented across all U.S. states, has revolutionized diagnosis by enabling identification of affected infants before they develop life-threatening infections. Screening uses the TREC (T cell receptor excision circle) assay, which quantifies circular DNA fragments excised during T cell receptor rearrangement in the thymus. Low TREC levels indicate T cell lymphopenia from any cause, including SCID, DiGeorge syndrome, and other conditions. Infants with positive screens require urgent evaluation including lymphocyte subset analysis and genetic testing. Early diagnosis enables early treatment, and outcomes of hematopoietic stem cell transplantation for SCID are dramatically better when performed before three months of age and before significant infections develop.

<image> Panel A: SCID genetic types showing X-linked SCID (IL2RG mutation affecting common gamma chain, T-B+NK-), ADA deficiency (toxic metabolite accumulation, T-B-NK-), RAG1/2 deficiency (impaired V(D)J recombination, T-B-NK+), and IL-7R deficiency (T-B+NK+), with cellular profiles and underlying mechanisms for each Panel B: DiGeorge syndrome showing 22q11.2 deletion with TBX1 gene, pharyngeal pouch development defects, CATCH-22 features (cardiac conotruncal defects, characteristic facies, thymic aplasia/hypoplasia, cleft palate, hypocalcemia), and spectrum from complete (rare, severe) to partial (common, mild immunodeficiency) Panel C: Newborn SCID screening concept showing TREC production during thymic T cell development, Guthrie card blood spot collection, TREC quantification by PCR, interpretation of low TRECs as T cell lymphopenia requiring evaluation, and the impact on outcomes through early diagnosis enabling early transplantation Panel D: Clinical presentation comparison showing SCID (early-onset severe opportunistic infections, failure to thrive, absence of lymphoid tissue) versus partial T cell defects (later onset, less severe infections, variable presentations), with emphasis on urgency of SCID diagnosis </image>

V. Combined Immunodeficiencies

Combined immunodeficiencies (CID) affect both T and B cell compartments but with less complete loss of T cell function than SCID, resulting in varied clinical presentations that may include immunodeficiency, autoimmunity, and other features depending on the specific genetic defect. These disorders are sometimes called "leaky SCID" when they result from hypomorphic mutations in SCID-associated genes, allowing some residual T cell function. The boundary between CID and SCID is somewhat arbitrary, but CID patients typically survive beyond infancy without transplantation, though with significant morbidity from infections and immune dysregulation.

Wiskott-Aldrich syndrome (WAS) is an X-linked combined immunodeficiency caused by mutations in the WAS gene encoding WASP (Wiskott-Aldrich syndrome protein), which regulates actin cytoskeleton reorganization in hematopoietic cells. The classic triad includes eczema, thrombocytopenia with characteristically small platelets (low mean platelet volume), and immunodeficiency. The immunodeficiency involves impaired T cell and B cell function, with progressive decline over time, defective antibody responses to polysaccharide antigens, and variable decreases in serum immunoglobulins (often with elevated IgA and IgE). Patients are susceptible to bacterial, viral, and opportunistic infections. Additional complications include autoimmunity (particularly autoimmune hemolytic anemia and vasculitis) and markedly increased risk of lymphoma and other malignancies. Hematopoietic stem cell transplantation is curative and recommended for patients with severe disease, while gene therapy has shown promise in clinical trials.

Ataxia-telangiectasia (AT) results from mutations in the ATM gene, which encodes a kinase central to the DNA damage response. Clinical features include progressive cerebellar ataxia beginning in early childhood, oculocutaneous telangiectasias appearing later, immunodeficiency, extreme sensitivity to ionizing radiation, and markedly elevated cancer risk (particularly lymphoid malignancies). The immunodeficiency is variable, often manifesting as IgA deficiency, IgG2 subclass deficiency, or more significant combined defects in severely affected patients. T cells show defective signaling and reduced diversity due to impaired V(D)J recombination, which requires DNA double-strand breaks. Patients must avoid unnecessary radiographic studies due to radiation sensitivity. Management is supportive, with immunoglobulin replacement for those with significant antibody deficiency, prophylactic antibiotics, and cancer surveillance.

Hyper-IgE syndrome, classically caused by dominant-negative mutations in STAT3 (signal transducer and activator of transcription 3), presents with markedly elevated serum IgE, eczema, and recurrent staphylococcal skin and pulmonary infections. A distinctive feature is the formation of "cold" abscesses that lack the typical inflammatory signs of warmth and erythema, reflecting impaired neutrophil chemotaxis. Pulmonary infections frequently lead to pneumatocele formation. Patients also exhibit non-immunological features including characteristic facial appearance, retained primary teeth, hyperextensible joints, minimal trauma fractures, and scoliosis, reflecting STAT3's role in bone and connective tissue development. Chronic mucocutaneous candidiasis (CMC) is another combined immunodeficiency primarily affecting Th17-mediated immunity at mucosal surfaces, caused by various genetic defects in the IL-17 pathway or, when associated with autoimmune polyendocrinopathy, by AIRE mutations leading to neutralizing autoantibodies against IL-17 and IL-22.

<image> Panel A: Wiskott-Aldrich syndrome showing WAS gene mutation affecting WASP protein function in actin cytoskeleton regulation, the classic triad (eczema, thrombocytopenia with small platelets, immunodeficiency), progressive immune dysfunction, autoimmunity, and malignancy risk, with treatment options including HSCT and gene therapy Panel B: Ataxia-telangiectasia showing ATM gene function in DNA damage response, clinical features (progressive ataxia shown on timeline, telangiectasias on conjunctiva and skin, immunodeficiency, cancer susceptibility), radiation sensitivity mechanism, and variable immunodeficiency patterns Panel C: Hyper-IgE syndrome (STAT3 deficiency) showing signaling pathway affected, immunological features (elevated IgE, eczema, staphylococcal infections, cold abscesses, pneumatoceles), and non-immunological features (facial features, retained teeth, skeletal abnormalities), illustrating the multisystem nature Panel D: Chronic mucocutaneous candidiasis showing various genetic causes affecting the IL-17 pathway (IL-17RA, IL-17F, ACT1 mutations, AIRE-associated anti-IL-17 antibodies), clinical presentation with persistent Candida affecting skin, nails, and mucous membranes, and the specific Th17 defect underlying susceptibility </image>

VI. Phagocyte Disorders

Phagocyte disorders affect the function of neutrophils, monocytes, and macrophages, resulting in susceptibility to bacterial and fungal infections, particularly affecting skin, lymph nodes, lungs, liver, and bone. These disorders can involve defects in phagocyte production (quantitative disorders), migration to sites of infection (adhesion defects), or intracellular killing mechanisms (qualitative disorders). The pattern of infections differs from antibody deficiencies, with frequent abscess formation, poor wound healing, and a characteristic spectrum of pathogens including Staphylococcus aureus, gram-negative enteric bacteria, and fungi, especially Aspergillus.

Chronic granulomatous disease (CGD) results from defects in the NADPH oxidase complex, which generates superoxide and other reactive oxygen species essential for intracellular killing of phagocytosed organisms. The most common form is X-linked, caused by mutations in CYBB encoding gp91phox (approximately 65% of cases), while autosomal recessive forms result from mutations in genes encoding other oxidase components (p47phox, p67phox, p22phox). Patients develop recurrent severe infections with catalase-positive organisms, which include Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia, and Aspergillus species. Catalase-positive organisms are pathogenic because they destroy their own hydrogen peroxide, preventing CGD phagocytes from using this pathogen-derived source for oxidative killing, whereas catalase-negative bacteria like Streptococci provide hydrogen peroxide that can partially compensate for the NADPH oxidase defect.

Leukocyte adhesion deficiencies (LAD) comprise a group of disorders affecting leukocyte migration from blood to tissues. LAD type 1, the most common, results from deficiency of CD18, the beta2 integrin chain shared by LFA-1, Mac-1, and CR4, which are essential for firm adhesion to endothelium and transmigration. Clinical features include delayed umbilical cord separation (beyond three weeks), recurrent severe bacterial infections without pus formation despite marked peripheral leukocytosis (reflecting inability of neutrophils to exit the bloodstream), and impaired wound healing. LAD type 2 results from defects in fucose metabolism affecting selectin ligand synthesis, while LAD type 3 involves kindlin-3 deficiency affecting integrin activation and also causes bleeding. Diagnosis of LAD-1 is made by flow cytometry demonstrating absent or reduced CD18 expression on leukocytes, and hematopoietic stem cell transplantation is curative.

Chediak-Higashi syndrome is a rare autosomal recessive disorder caused by mutations in the LYST gene, which regulates lysosomal trafficking. The hallmark is giant granules in leukocytes (and melanosomes in melanocytes) resulting from abnormal vesicle fusion. Patients exhibit partial oculocutaneous albinism, bleeding tendency, neurological abnormalities, and recurrent pyogenic infections. Many patients eventually develop an "accelerated phase" characterized by lymphoproliferative syndrome with hemophagocytosis, which is often fatal. Cyclic neutropenia, caused by mutations in ELANE encoding neutrophil elastase, produces regular oscillations in neutrophil counts with a period of approximately 21 days. During the nadir, which typically lasts three to five days, patients are susceptible to severe infections and mouth ulcers. G-CSF treatment shortens and moderates the neutropenic periods, improving quality of life and preventing serious infections.

<image> Panel A: Chronic granulomatous disease showing NADPH oxidase complex assembly on the phagosome membrane (gp91phox, p22phox, p47phox, p67phox, Rac), superoxide generation and conversion to microbicidal reactive oxygen species, catalase-positive organism concept explaining pathogen spectrum, and diagnostic testing (DHR flow cytometry showing absent oxidative burst) Panel B: Leukocyte adhesion deficiency type 1 showing normal leukocyte recruitment cascade (rolling via selectins, firm adhesion via integrins, transmigration), CD18/beta2 integrin deficiency blocking firm adhesion, clinical features (delayed cord separation, absent pus despite leukocytosis, severe infections), and diagnostic flow cytometry showing absent CD18 Panel C: Chediak-Higashi syndrome showing LYST gene function in vesicle trafficking, giant granules in neutrophils and giant melanosomes causing partial albinism, clinical features (infections, bleeding, neurological disease), and the accelerated phase with hemophagocytic lymphohistiocytosis Panel D: Cyclic neutropenia showing ELANE mutation, regular 21-day oscillations in neutrophil counts with severe neutropenic nadirs lasting 3-5 days, clinical manifestations during nadirs (fever, oral ulcers, severe infections), and G-CSF treatment effect on cycle amplitude </image>

VII. Complement Deficiencies

Complement deficiencies can affect any component of the complement system, resulting in distinct clinical syndromes depending on which pathway and which specific component is deficient. Classical pathway component deficiencies (C1q, C1r, C1s, C2, C4) are strongly associated with autoimmune disease, particularly systemic lupus erythematosus, while terminal pathway deficiencies (C5-C9) cause specific susceptibility to Neisseria infections. C3 deficiency, affecting the central component where all pathways converge, causes both infection susceptibility and autoimmune disease. Regulatory protein deficiencies cause uncontrolled complement activation with distinct syndromes including hereditary angioedema and atypical hemolytic uremic syndrome.

Classical pathway deficiencies predispose to SLE-like illness through impaired clearance of apoptotic cells and immune complexes, which are normally opsonized by early complement components for phagocytic removal. C1q deficiency carries the strongest association with lupus, with over 90% of affected individuals developing lupus or lupus-like disease, often severe and early in onset. C2 deficiency is the most common classical pathway deficiency, and while the majority of affected individuals are healthy, there is increased risk of SLE, recurrent sinopulmonary infections with encapsulated bacteria, and invasive pneumococcal disease. C4 deficiency similarly predisposes to lupus and infections. The lupus associated with complement deficiency often has distinctive features including early onset, prominent cutaneous involvement, and lower frequency of anti-dsDNA antibodies compared to typical lupus.

Terminal pathway deficiencies (C5, C6, C7, C8, or C9) cause specific susceptibility to invasive Neisseria infections (meningococcal and gonococcal disease), reflecting the unique dependence of defense against Neisseria on membrane attack complex-mediated lysis. Affected individuals have up to 1000-fold increased risk of meningococcal meningitis and may experience recurrent episodes. Interestingly, mortality from meningococcal disease may be lower in complement-deficient patients, possibly because the inflammatory response is attenuated in the absence of complement activation products. All patients with terminal pathway deficiencies should receive meningococcal vaccination (quadrivalent conjugate and serogroup B vaccines) and should be educated about the need for prompt evaluation of febrile illnesses. Screening for complement deficiency should be considered in any patient with invasive Neisseria infection, recurrent Neisseria infections, or infection with unusual Neisseria species.

Hereditary angioedema (HAE) results from deficiency or dysfunction of C1 inhibitor, a serine protease inhibitor that regulates not only the classical complement pathway (by inhibiting C1r and C1s) but also the contact activation system (by inhibiting kallikrein and factor XIIa). The clinical syndrome is characterized by recurrent episodes of nonpruritic, non-urticarial angioedema affecting subcutaneous tissues (face, extremities, genitals) and submucosal tissues (gastrointestinal tract causing abdominal pain, and larynx causing potentially fatal airway obstruction). The edema results from uncontrolled bradykinin generation rather than from complement activation. Management includes acute treatment with C1 inhibitor concentrate, bradykinin receptor antagonist (icatibant), or kallikrein inhibitor (ecallantide), and prophylaxis for patients with frequent attacks using C1 inhibitor, lanadelumab (anti-kallikrein antibody), or berotralstat (oral kallikrein inhibitor).

<image> Panel A: Complement pathway diagram annotated with clinical associations of each deficiency: classical pathway defects (C1q, C2, C4) associated with SLE and infections, C3 deficiency causing severe infections and autoimmunity, terminal pathway defects (C5-C9) causing Neisseria susceptibility, and the explanation for each pattern Panel B: Classical pathway deficiency and lupus connection showing apoptotic cell generating membrane blebs with self-antigens, C1q binding and marking for clearance, impaired clearance in C1q deficiency leading to autoantigen exposure and autoimmunity, with clinical features of complement-associated lupus Panel C: Terminal pathway deficiency showing normal MAC formation and Neisseria lysis, absent MAC with C5-C9 deficiency allowing Neisseria survival and dissemination, the paradox of potentially reduced mortality despite increased infection frequency, and vaccination recommendations Panel D: Hereditary angioedema pathophysiology showing C1 inhibitor deficiency, uncontrolled contact system activation leading to bradykinin generation, bradykinin-mediated vascular permeability causing angioedema, typical clinical presentation (facial swelling, abdominal attacks, laryngeal edema), and treatment options targeting different points in the pathway </image>

VIII. Acquired Immunodeficiency: HIV/AIDS

Human immunodeficiency virus (HIV) infection represents the most significant acquired immunodeficiency worldwide, with approximately 38 million people living with HIV globally. HIV is a retrovirus that specifically infects and destroys CD4+ T cells, leading to progressive immunodeficiency and, without treatment, to acquired immunodeficiency syndrome (AIDS). The development of effective antiretroviral therapy has transformed HIV from a fatal diagnosis to a manageable chronic condition, but the global impact remains enormous, and understanding HIV immunopathogenesis is essential for clinical care and ongoing efforts toward cure and vaccine development.

HIV virology and lifecycle provide targets for therapeutic intervention and explain the pathogenesis of immunodeficiency. HIV is a lentivirus with an RNA genome that is reverse transcribed to DNA and integrated into the host cell genome. Entry requires binding to CD4 (via gp120) followed by binding to a coreceptor, either CCR5 (used by most transmitted viruses) or CXCR4 (emerging in later disease). The integrated provirus can remain latent or actively produce new virions. Active replication kills host CD4+ T cells directly through cytopathic effects and indirectly through immune activation and bystander killing. The establishment of a latent reservoir in resting memory CD4+ T cells presents the major obstacle to cure, as these cells harbor integrated provirus without expressing viral proteins, making them invisible to immune surveillance and resistant to antiretroviral therapy.

The natural history of untreated HIV infection progresses through distinct clinical stages reflecting the dynamic between viral replication and immune responses. Acute HIV infection, occurring two to four weeks after exposure, is characterized by high viral load and flu-like symptoms (fever, lymphadenopathy, rash, pharyngitis); many cases are not recognized. During acute infection, massive depletion of gut-associated CD4+ T cells occurs, with particular loss of Th17 cells important for mucosal barrier integrity. The immune response partially controls viremia, establishing a viral "set point," and the patient enters the chronic or clinical latency phase, which can last years with gradual CD4 decline. AIDS is defined by CD4 count below 200 cells/microL or the occurrence of AIDS-defining conditions, which include opportunistic infections (Pneumocystis pneumonia, cryptococcal meningitis, toxoplasmosis, CMV disease, MAC), malignancies (Kaposi sarcoma, non-Hodgkin lymphoma, cervical cancer), and other conditions (HIV encephalopathy, wasting syndrome).

Modern HIV management with combination antiretroviral therapy (ART) has dramatically improved outcomes, enabling near-normal life expectancy when treatment is initiated early and maintained. The goal of treatment is durable suppression of viral load to undetectable levels (below 50 copies/mL), which allows immune reconstitution, prevents AIDS-defining events, and eliminates sexual transmission (undetectable equals untransmittable, U=U). Current first-line regimens typically combine two nucleoside reverse transcriptase inhibitors with an integrase inhibitor and are well tolerated with once-daily dosing. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs is highly effective for HIV prevention in high-risk individuals. Monitoring includes regular viral load measurement to confirm suppression and CD4 counts to assess immune status, with prophylaxis against opportunistic infections indicated when CD4 counts are low.

<image> Panel A: HIV lifecycle diagram showing viral entry (gp120-CD4 binding, coreceptor engagement, fusion), reverse transcription of RNA to DNA, nuclear import and integration, viral gene expression, assembly and budding, with antiretroviral drug classes annotated at their sites of action (entry inhibitors, NRTIs, NNRTIs, integrase inhibitors, protease inhibitors) Panel B: Natural history of untreated HIV showing acute phase (high viremia, symptoms, massive gut CD4 depletion), set point establishment with partial immune control, chronic phase (asymptomatic, gradual CD4 decline), and AIDS (CD4 <200, opportunistic infections), with typical timeline and CD4/viral load graphs Panel C: AIDS-defining conditions organized by CD4 threshold: below 200 (Pneumocystis, esophageal candidiasis, Kaposi sarcoma), below 100 (toxoplasmosis, cryptococcosis, cryptosporidiosis), below 50 (CMV disease, MAC, CNS lymphoma), with representative imaging or clinical features for each Panel D: Modern HIV management showing ART regimen components, treatment goals (viral suppression, immune reconstitution, U=U), monitoring strategy (viral load, CD4 count), prevention strategies (PrEP, treatment as prevention), and the obstacle to cure posed by the latent reservoir in resting memory CD4 T cells </image>

IX. Evaluation of Immunodeficiency

The evaluation of suspected immunodeficiency requires systematic clinical assessment followed by appropriate laboratory testing guided by the pattern of infections and clinical features. A thorough history should document the type, frequency, severity, and causative organisms of infections; response to antibiotic treatment; need for hospitalization or intravenous antibiotics; and any complications such as bronchiectasis or organ damage. Family history is essential, as many primary immunodeficiencies are inherited, and consanguinity suggests autosomal recessive disorders. Past medical history should include vaccine complications (suggesting T cell defects), autoimmune disease (associated with several immunodeficiencies), and growth parameters (failure to thrive suggests combined or T cell defects).

Initial laboratory evaluation should include tests that efficiently screen for major categories of immunodeficiency. Complete blood count with differential identifies lymphopenia (suggesting T cell defects), neutropenia, and thrombocytopenia (small platelets in WAS). Quantitative immunoglobulins (IgG, IgA, IgM) detect most antibody deficiencies; IgE may be added if hyper-IgE syndrome is suspected. HIV testing should be considered in any adult or at-risk individual with suspected immunodeficiency. Vaccine responses (specific antibody levels to tetanus, diphtheria, and pneumococcal antigens, measured before and after vaccination if initial levels are low) assess functional humoral immunity. These basic tests will identify or suggest most immunodeficiencies and guide further targeted evaluation.

Advanced testing is directed by initial findings and clinical suspicion. Lymphocyte subset analysis by flow cytometry quantifies CD3+ T cells, CD4+ and CD8+ subsets, B cells (CD19+), and NK cells (CD16+CD56+), identifying lymphopenia and characterizing combined defects. T cell proliferation assays assess functional responses to mitogens and antigens. For suspected phagocyte defects, dihydrorhodamine (DHR) flow cytometry has replaced the nitroblue tetrazolium (NBT) test for diagnosing CGD, measuring oxidative burst in individual neutrophils. Complement evaluation includes CH50 (total classical pathway function) and AH50 (alternative pathway), with individual component measurement if these screening tests are abnormal. Genetic testing, increasingly performed early in evaluation using next-generation sequencing panels, can definitively diagnose many conditions and is essential for genetic counseling and identifying candidates for targeted therapies including gene therapy.

Treatment principles for immunodeficiency depend on the specific diagnosis but include immunoglobulin replacement for antibody deficiencies (administered intravenously or subcutaneously), antimicrobial prophylaxis tailored to the infection risk (such as TMP-SMX for Pneumocystis prophylaxis in T cell defects), avoidance of live vaccines in T cell deficiencies, and definitive correction through hematopoietic stem cell transplantation for severe combined immunodeficiencies, CGD, WAS, and other serious disorders. Gene therapy is emerging as an alternative to transplantation for selected conditions, with approved therapies for ADA-SCID and promising results for X-linked SCID, WAS, and CGD in clinical trials. Early diagnosis through newborn screening and prompt initiation of appropriate treatment dramatically improves outcomes.

<image> Panel A: Clinical evaluation framework showing history elements (infection types, frequency, severity, pathogens, treatment response, hospitalizations, complications, vaccine reactions), physical examination findings (lymphoid tissue presence/absence, growth parameters, dysmorphic features), and family history assessment (inheritance pattern, consanguinity, deceased siblings) Panel B: Tiered laboratory evaluation showing first-tier tests (CBC with differential, quantitative Ig, HIV, vaccine titers), second-tier tests directed by initial findings (lymphocyte subsets, specific antibody responses, complement studies, DHR), and third-tier definitive testing (genetic panels, research testing), with interpretation guidance Panel C: DHR flow cytometry for CGD diagnosis showing normal neutrophils with bright fluorescence after PMA stimulation indicating oxidative burst, CGD neutrophils with absent shift, and carrier detection in X-linked CGD showing bimodal population Panel D: Treatment algorithm organized by diagnosis: antibody deficiencies (IVIG or SCIG replacement, target trough IgG levels), T cell and combined defects (HSCT for severe, gene therapy for selected, prophylaxis and supportive care), phagocyte defects (antimicrobial prophylaxis, HSCT for severe CGD), and complement defects (vaccination, education, surveillance) </image>

X. Treatment Approaches

Immunoglobulin replacement therapy is the cornerstone of treatment for antibody deficiencies, providing passive antibody protection by regular administration of pooled human IgG collected from thousands of donors to ensure broad antibody coverage. Intravenous immunoglobulin (IVIG) is typically administered every three to four weeks in a medical setting, while subcutaneous immunoglobulin (SCIG) allows more frequent self-administration at home (weekly or biweekly) with more stable serum levels and potentially fewer systemic side effects. The goal is to achieve trough IgG levels that minimize infections, typically above 500-800 mg/dL, though some patients require higher targets. Immunoglobulin replacement is lifelong for permanent antibody deficiencies and dramatically reduces infection frequency and severity, preventing progressive lung damage.

Hematopoietic stem cell transplantation (HSCT) provides definitive curative treatment for many severe primary immunodeficiencies by replacing the defective immune system with donor-derived cells. HSCT is indicated for SCID (where it is urgent and potentially life-saving), Wiskott-Aldrich syndrome, chronic granulomatous disease, and other severe conditions. Outcomes depend heavily on donor matching, patient age and clinical status at transplantation, and the specific underlying condition. For SCID, transplantation before three months of age and before development of infections yields the best outcomes, with survival exceeding 90% with matched sibling donors. Conditioning regimens vary from myeloablative (full donor engraftment) to reduced intensity or no conditioning, depending on the underlying disease and the degree of chimerism required for cure.

Gene therapy has emerged as an alternative to transplantation for selected immunodeficiencies, offering the advantage of autologous cells without risk of graft-versus-host disease or need for immunosuppression. The approach involves collecting patient hematopoietic stem cells, genetically modifying them ex vivo to correct the defect (using viral vectors or gene editing), and reinfusing the corrected cells after conditioning. Strimvelis, a gene therapy for ADA-SCID, was the first approved gene therapy for primary immunodeficiency. Clinical trials have shown promising results for X-linked SCID (though early trials caused leukemia from insertional mutagenesis, newer vector designs have improved safety), Wiskott-Aldrich syndrome, and chronic granulomatous disease. Gene editing approaches using CRISPR technology are in development and may enable even more precise correction.

Antimicrobial prophylaxis is essential for many immunodeficiencies to prevent the most likely and dangerous infections. Patients with T cell defects typically receive trimethoprim-sulfamethoxazole for Pneumocystis prophylaxis and may receive antifungal prophylaxis. CGD patients benefit from TMP-SMX (which concentrates in phagocytes) and itraconazole for Aspergillus prophylaxis; IFN-gamma reduces infections in some patients though its use has declined. Complement-deficient patients should receive meningococcal vaccines (conjugate and serogroup B). HIV-infected individuals with low CD4 counts receive prophylaxis against opportunistic infections based on thresholds (TMP-SMX when CD4 below 200, MAC prophylaxis when CD4 below 50). Live vaccines must be avoided in T cell deficiencies, and household contacts should receive inactivated instead of live polio vaccine to prevent vaccine-acquired poliomyelitis.

<image> Panel A: Immunoglobulin replacement therapy showing IVIG administration (clinic-based, every 3-4 weeks, rapid infusion, peak and trough dynamics) versus SCIG (home-based, weekly, subcutaneous infusion, stable levels), target trough levels, and monitoring approach with adjustment based on infection frequency Panel B: HSCT for immunodeficiency showing indications (SCID, WAS, CGD, other severe PIDs), donor options (matched sibling, matched unrelated, haploidentical, cord blood) with outcomes, conditioning intensity spectrum, and the critical importance of early transplant for SCID illustrated by survival curves based on age at transplant Panel C: Gene therapy concept showing stem cell collection, ex vivo gene transfer using viral vector or gene editing, corrected stem cell expansion, conditioning, and reinfusion, with current approved/investigational gene therapies (ADA-SCID approved, X-SCID and WAS in trials) and safety considerations Panel D: Prophylaxis strategies organized by condition: T cell defects (TMP-SMX for PCP, antifungals, avoid live vaccines), CGD (TMP-SMX, itraconazole, IFN-gamma consideration), complement deficiency (meningococcal vaccines), HIV (OI prophylaxis by CD4 thresholds), with specific agents and indications </image>

Summary

• Immunodeficiencies are classified as primary (genetic) or secondary (acquired), with patterns of infection suggesting the affected immune component
• B cell and antibody deficiencies are the most common PIDs; XLA (BTK mutation, absent B cells) and CVID (heterogeneous, adult onset, complications beyond infection) are key examples
• SCID is a medical emergency requiring early diagnosis through TREC newborn screening and urgent HSCT; X-linked (IL2RG) and ADA deficiency are common forms
• DiGeorge syndrome (22q11.2 deletion) causes thymic hypoplasia with variable T cell deficiency plus cardiac defects and hypocalcemia
• Combined immunodeficiencies include WAS (eczema, thrombocytopenia, immunodeficiency), AT (ataxia, telangiectasia, radiation sensitivity), and STAT3 hyper-IgE syndrome
• CGD involves defective NADPH oxidase causing susceptibility to catalase-positive organisms; diagnosed by DHR flow cytometry
• LAD-1 features delayed cord separation, absent pus formation despite marked leukocytosis, due to CD18 deficiency
• Classical complement deficiencies (C1q, C2, C4) cause SLE; terminal deficiencies (C5-C9) cause Neisseria susceptibility; C1 inhibitor deficiency causes HAE
• HIV infects CD4+ T cells, causing progressive immunodeficiency; ART achieves viral suppression, immune reconstitution, and prevents transmission
• Treatment includes IVIG/SCIG replacement, HSCT for severe conditions, gene therapy for selected disorders, and tailored antimicrobial prophylaxis

Key Terms

This content is subject to the MIT License. © 2024–2026 Hibbert School of Medicine.

Read this lecture as Markdown