Immunodeficiencies and HIV

IMMUNODEFICIENCIES

  • Dr. Francina Towne

    • Course: IHL, RVU

    • Class of 2027

READING ASSIGNMENT

  • Textbook: Basic Immunology: Functions & Disorders of the Immune System, Abbas & Lichtman

    • Chapter 12: All on Immunodeficiencies

LEARNING OBJECTIVES

  • Describe the mechanistic defects in B cell, T cell, and innate immunodeficiencies.

  • Describe the pathophysiology for each type of immunodeficiency.

  • Compare and contrast the functional presentation of the immunodeficiencies.

  • Identify the major components of HIV and the immune response to HIV.

  • Discuss the current state of HIV infection, health disparities, and vaccine development in the US.

PRIMARY AND SECONDARY IMMUNODEFICIENCIES

  • Primary Immunodeficiencies (Congenital/Inherited)

    • Over 150+ described so far

    • Types:

      • Dominant

      • Recessive

      • X-linked

  • Secondary Immunodeficiencies (Acquired)

    • Not due to defective genes

    • Caused by:

    • Environmental factors

    • Immune suppressive drugs

    • Infection

PRIMARY IMMUNODEFICIENCIES TO KNOW

  • C1 esterase inhibitor deficiency

  • Early and late complement deficiencies

  • XLA (X-linked agammaglobulinemia)

  • AIRE deficiency

  • SCID (Severe Combined Immunodeficiency)

  • Hyper-IgM syndrome

  • Wiskott-Aldrich syndrome

  • Leukocyte adhesion deficiency

  • Chediak-Higashi syndrome

  • Chronic Granulomatous Disease (CGD)

  • DiGeorge Syndrome

  • Deficiencies in MHC Class I or II

  • IFNgamma deficiency

  • Any others covered by other professors in their lectures.

FEATURES OF INNATE AND ADAPTIVE IMMUNODEFICIENCIES

  • Histopathology and Laboratory Abnormalities:

    • B cell deficiencies

    • Absent or reduced follicles and germinal centers in lymphoid organs.

    • Reduced serum immunoglobulin (Ig) levels.

    • T cell deficiencies

    • May show reduced T cell zones in lymphoid organs.

    • Innate immune deficiencies

    • Reduced DTH reactions to common antigens.

    • Defective T cell proliferative responses to mitogens in vitro.

    • Variable outcomes depending on which component of innate immunity is defective.

  • Common Infectious Consequences:

    • B cell deficiencies: Pyogenic bacterial infections, enteric bacterial and viral infections.

    • T cell deficiencies: Viral and other intracellular microbial infections like Pneumocystis jiroveci.

    • Innate deficiencies: Variable infections including pyogenic bacterial and viral infections.

GENETIC DEFECTS IN LYMPHOCYTE MATURATION

  • Genetic deficiencies that block lymphocyte maturation are present.

  • The specific disease names associated with these genetic defects were briefly mentioned but not specified.

  • Patients required knowledge of which genes are expressed on all nucleated cells (not just immune cells).

SEVERE COMBINED IMMUNODEFICIENCY (SCID)

  • Types of SCID:

    • X-linked SCID

    • Markedly decreased T cells and normal or increased B cells; reduced serum Ig.

    • Mechanism: Cytokine receptor common gamma chain gene mutations, leading to defective T cell maturation due to lack of IL-7 signals.

    • Autosomal Recessive SCID

    • Caused by ADA (Adenosine Deaminase) or PNP (Purine Nucleoside Phosphorylase) deficiency.

    • Leads to the accumulation of toxic metabolites in lymphocytes, causing reduced T and B cells.

    • Other autosomal recessive SCID can have various causes like mutations in RAG genes.

CASE STUDY: ROBERT JOSEPH

  • Patient History: 6-month-old boy with respiratory distress, lymphadenitis, oral candidiasis, and hepatomegaly.

  • Parents: Consanguineous; previous child died of sepsis at 7 months with similar symptoms.

  • Clinical Data:

    • IgG: 418 mg/dL (normal range 620-1400 mg/dL)

    • WBCs: 3200/mm3 (normal 4500-10000/mm3)

    • IgM: 54 mg/dL (normal 45-250 mg/dL)

    • IgA: 95 mg/dL (normal 80-350 mg/dL)

    • CD19+: 2%, CD3+: 10%, CD4+: 6%, CD8+: 12%, CD56+: 93%.

  • Treatment: IVIG and antibiotics initiated; patient did not respond and passed away.

  • Diagnosis: T–B–NK+ SCID confirmed through sequencing of RAG1 and RAG2 genes. Homozygous mutations found in the RAG2 gene; mutations account for 3-4% of SCID cases.

WISKOTT-ALDRICH SYNDROME

  • Genetics: X-linked recessive; mutation in the WAS gene.

  • Pathophysiology: WAS-protein is vital for cytoskeleton reorganization in WBCs and platelets.

  • Symptoms:

    • Eczema, petechia, recurrent infections, bloody diarrhea, and thrombocytopenia.

  • Platelets and WBCs: Poor development/migration; treatment includes Bone Marrow Transplant (BMT).

LYMPHOCYTE MATURATION DEFECTS

  • B cell Immunodeficiencies:

    • X-linked agammaglobulinemia: Decreased serum Ig and heavy chain deficiency.

    • Deficiency of IgG subclasses; possible absence of IgA or IgE.

  • T cell Maturation Disorders:

    • DiGeorge Syndrome:

    • Reduced T cells; normal B cells; normal or decreased serum Ig.

    • Mechanism: Block in maturation due to a chromosomal deletion at 14q32; leads to thymic hypoplasia.

FOLLOW UP CASE: BILL GRIGNARD

  • History: Bill had frequent infections during infancy; serum immunoglobulin levels tested at age 2.

    • Restored IgG levels with gamma globulin injections; remained healthy overall except for occasional infections and became a medical student.

    • Concerns about B cell or T cell dysfunction were raised based on his immunologic profile.

XLA - X-LINKED AGAMMAGLOBULINEMIA

  • Pathophysiology: Susceptible to encapsulated bacteria and enteroviruses.

  • Mechanism: Encapsulated bacteria require antibody opsonization for phagocyte recognition.

    • Enteroviruses are neutralized by antibody responses in mucosal surfaces.

  • Treatment: Regular gamma globulin injections.

DEFECTS IN LYMPHOCYTE ACTIVATION AND EFFECTOR FUNCTIONS

  • Mechanisms such as mutations in various genes, impacting:

    • T cell receptor signaling.

    • Helper T cell activation for B cell and macrophage responses (deficiency in CD40 ligand).

    • Th1 and Th17 differentiation defects.

IFN-GAMMA RECEPTOR DEFICIENCY

  • Cytokine Role: Major cytokine produced by activated T cells; activates macrophages.

  • Mutations:

    • Recessive: More severe, leading to loss of function.

    • Dominant: Truncated protein unable to bind signaling partners, resulting in reduced response.

  • Clinical Implications: Higher susceptibility to Mycobacterium infections.

IL-12 DEFICIENCY

  • IL-12 receptor deficiency leads to vulnerability to intracellular infections due to compromised immune responses.

CASE STUDY: DENNIS FAWCETT

  • History: 5 y/o with recurrent infections; sinus infection led to further evaluation.

  • Clinical Findings:

    • Low IgG levels, undetectable IgA, normal IgM; absence of germinal centers in lymph node biopsy.

HYPER-IGM IMMUNODEFICIENCY

  • Genetic Defects: Five types leading to inability to class switch.

    • Most common: X-linked hyper-IgM, defect in CD40L expression.

  • Clinical Features:

    • Prone to bacterial and opportunistic infections like Pneumocystis jiroveci pneumonia.

DEFECTS IN INNATE IMMUNITY

  • Common Disorders:

    • Chronic Granulomatous Disease, Leukocyte Adhesion Deficiencies, Chediak-Higashi syndrome, and complement deficiencies.

    • Mechanisms involve mutations affecting reactive oxygen production, leukocyte adhesion, and lysosomal function.

HISTOLOGICAL AND FUNCTIONAL TESTS

  • Importance of assessing immune cell counts, immunoglobulin levels, and complement function.

  • Assessing functional capabilities of leukocyte responses through various tests like NBT and DHR assays.

ACQUIRED (SECONDARY) IMMUNODEFICIENCIES

  • Causes:

    • Human Immunodeficiency Virus (HIV) infection, irradiation, chemotherapy, malnutrition, splenectomy, and cancers.

  • Mechanisms include depletion or functional impairment of lymphocyte populations.

HIV AND AIDS

  • Current Issues: Over half of young Americans with HIV do not know their status. CDC data indicates ongoing disparities in infection rates, particularly among African Americans and the transgender community.

  • Vaccine Development: Major challenges persist due to the virus's high mutation rate and ability to infect immune cells.

HIV TRANSMISSION AND ENTRY

  • Modes of Infection: Sexual contact, IV drug use, breastfeeding, transfusion, and vertical transmission.

  • Unique Aspects of HIV: Causal link to long-term health complications; requires nuanced understanding of disease progression and immune response failure.

QUESTIONS AND DISCUSSION POINTS

  • Key aspects to assess within immunodeficiencies, differences between primary and secondary types, and unique characteristics of HIV.

  • Understanding treatment implications and considerations surrounding the management of immunodeficient patients.

ADDITIONAL TOPICS FOR DISCUSSION

  • Understanding the psychosocial aspects of dealing with stigmas associated with HIV/AIDS.

  • Ensuring client-centered communication and compassionate care in clinical settings.

RECOMMENDATIONS FOR STUDY

  • Review key genetic mutations associated with various immunodeficiencies and their clinical implications.

  • Understand the pathophysiological mechanisms underlying different immunodeficiencies for case discussions.

  • Familiarize with the latest information on HIV/AIDS epidemiology, treatment, and prevention strategies.