Immunodeficiencies Lecture Notes

Immunodeficiencies

Introduction to Immunodeficiencies

  • Immunodeficiencies arise from the absence or impaired function of one or more components of the immune system.
  • The primary outcome is heightened vulnerability to infections.
  • The nature of infections is indicative of the specific immune component(s) that are deficient.
  • These are categorized into primary and secondary immunodeficiencies.

Primary Immunodeficiencies (PI)

  • Over 150 distinct primary immunodeficiencies exist, affecting approximately 500,000 individuals in the US.
  • These are caused by genetic or developmental defects.
  • Each PI manifests with unique symptoms, dependent on the specific deficiency within the immune defense system.
  • The severity of PIs varies, ranging from mild to fatal.
  • A common characteristic is the increased susceptibility to multiple infections.
  • Infections are a key indicator but not always the sole or primary health concern.
  • Some PIs correlate with other immune-related conditions, like anemia, arthritis, or autoimmune disorders.
  • Certain PIs extend beyond the immune system, impacting the heart, digestive system, or nervous system.
  • Some PIs can hinder growth and elevate cancer risk.
  • PIs can stem from defects in lymphocyte maturation, activation, and/or function, or in components of innate immunity.

Innate Immunity Deficiencies

  • Individuals are more prone to bacterial infections, especially those caused by encapsulated bacteria.
  • Defects commonly occur within phagocytosis or complement pathways.
  • Examples include Chronic Granulomatous Disease (CGD) and Hereditary angioedema (HAE).
Chronic Granulomatous Disease (CGD)
  • An inherited immunodeficiency affecting phagocyte function.
  • It's an X-linked defect in NADPH oxidase production, which reduces ROS production.
  • This leads to inefficient killing of ingested microorganisms, resulting in their persistence and spread.
Hereditary Angioedema (HAE)
  • Caused by a deficiency in C1 INH (C1 Inhibitor).
  • The protease activity of C1 remains continuously active, leading to unchecked production of C3 and C5 convertases.
  • This results in elevated concentrations of C3a and C5a, which are anaphylatoxins, leading to excessive swelling at bacterial entry sites.

B Cell Deficiencies

  • Patients are more susceptible to infections from certain bacteria, parasites, and viruses, where immunity relies mainly on antibody-mediated responses.
  • Examples include Giardia infections in the gut, polio virus infections in the gut, and infections with encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae type b.
Selective IgA Deficiency
  • Results from a block in B cell differentiation into IgA-secreting plasma cells, leading to little or no IgA production.
  • This can cause recurrent infections of the respiratory and genitourinary tracts.
X-linked Agammaglobulinemia (XLA)
  • Caused by mutations in Bruton’s tyrosine kinase (Btk).
  • This impairs the ability of B cells to synthesize and express a BCR.
  • It blocks the differentiation of pre-B cells into immature B cells, resulting in a lack of B cells, Igs in serum, and germinal centers in lymphoid tissues.
Hyper-IgM Syndrome
  • Results from mutations in the CD40L gene.
  • It's characterized by impaired antibody production, isotype switching, affinity maturation, and memory B cell generation.
  • Patients exhibit extremely high levels of IgM in their serum but very low levels of other isotypes.

T Cell Deficiencies

  • Patients are vulnerable to many viruses, intracellular microorganisms, and opportunistic infections.
  • Since T cells are often necessary for an effective B cell/humoral response, these patients often have deficiencies in both CMI and humoral immune responses.
Bare Lymphocyte Syndrome
  • Caused by a defect in promotor proteins for class II MHC genes, which inhibits the transcription of class II MHC genes.
  • This results in a reduced TH cell count due to failed selection in the thymus.
  • There is no antigen presentation to TH cells, leading to decreased humoral and CMI, including DTH responses.
  • Patients experience severe, recurrent infections with mortality in early childhood.
TAP Deficiency
  • Due to a genetic mutation causing a deficiency in TAP transport proteins.
  • Cells have a severely reduced ability to present antigens in class I MHC molecules.
  • CTL numbers are low, and their function is severely diminished, resulting in decreased cell-mediated immune (CMI) responses to intracellular foreign antigens, including intracellular microbes and tumor cells.

Severe Combined Immunodeficiencies (SCIDs)

  • Characterized by a severe deficit in both T and B lymphocytes.
  • Patients are highly susceptible to life-threatening viral, bacterial, and fungal infections early in life.
  • Patients lack T cells and NK cells; B cells are non-functional.
  • SCIDs can arise from various primary/genetic defects:
    1. X-linked SCID: Deficiency in CD132, the common  chain of several cytokine receptors, leads to defective receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, which are crucial for lymphocyte maturation and activation.
    2. RAG (recombination activating genes) Deficiency: Deficiencies in RAG enzymes, involved in somatic recombination of TCR and Igs, lead to failure of B and T cells to develop.

Secondary Immunodeficiencies

  • Worldwide, hundreds of millions of individuals are affected by secondary immunodeficiencies.
  • The most common causes include malnutrition, drugs, and infections.
  • The severity of the disease depends on the nature of the inducing agent, ranging from mild to life-threatening.
  • Some secondary immunodeficiencies are iatrogenic and necessary, such as immunosuppression for transplant patients.
Drugs
  • Any drug affecting the generation, maturation, and/or function of immune system cells can cause an immunodeficiency.
  • Notable examples include glucocorticoids (e.g., prednisone), calcineurin-inhibitors (e.g., cyclosporine), mycophenolate mofetil, antimetabolites (e.g., methotrexate), and alkylating agents (e.g., cyclophosphamide).
    • Calcineurin-inhibitors (e.g., cyclosporine): inhibit IL-2 synthesis
    • Mycophenolate mofetil: blocks guanine nucleotide synthesis → decreased DNA synthesis
    • Antimetabolites: inhibits folic acid synthesis → decreased DNA synthesis
    • Alkylating agents: DNA breakage → apoptosis
Infections
  • Various infections can lead to the development of a secondary immunodeficiency.
  • Many of these infections are transient, with the immunodeficiency corrected upon elimination of the infection.
  • HIV is a retrovirus that causes AIDS and has overshadowed all other causes of secondary immunodeficiencies in recent years.

HIV Structure and Replication

  • HIV is an enveloped retrovirus with a ssRNA genome containing mature viral enzymes and structural proteins important in the virus's life cycle and diagnosis.
  • HIV uses CD4 as its receptor and requires a co-receptor (either CXCR4 or CCR5) to enter host cells.
  • Host cells include helper T cells, monocytes/macrophages, and dendritic cells.
  • HIV binds to T cells via gp120/41 binding to CD4 & chemokine receptor (CXCR4).
  • HIV reverse transcribes RNA into DNA, then the viral DNA (provirus) integrates into the T cell genome.
  • Cytokine stimulation of the T cell induces transcription of the HIV provirus.
  • Synthesis of a proprotein is cleaved into functional proteins by viral protease.
  • New HIV particles bud off the host cell and can infect a new host cell.

HIV Spread

  • New HIV particles (virions) bud off an infected cell and infect new cells.
  • Viral spread can also occur due to cell-to-cell contact.
    • Infected APCs presenting antigen to T cells can pass on the virus due to close proximity, avoiding extracellular recognition by antibodies, typically occurring in secondary lymphatic tissues.

HIV Disease Progression

  • HIV infection is divided into stages:
    • Acute or Primary HIV infection: Occurs after viral transmission, resulting in seroconversion.
    • Clinical latency: With or without persistent generalized lymphadenopathy (PGL), characterized by a highly variable time period.
    • Early symptomatic HIV infection: Aka: Group B, Category B, AIDS-related complex (ARC), presenting with constitutional symptoms or various infections (but NOT AIDS-defining conditions).
    • AIDS: AIDS-defining conditions often present, with T cell counts below 200 cells/µL or <14% of total lymphocyte count; Advanced HIV infection = T cell counts below 50 cells/µL.
Acute (Primary) HIV Infection
  • Asymptomatic or presents with flu- or mono-like symptoms.
  • The virus enters the blood and infects monocytes, macrophages, and T cells, resulting in cytokine production and symptoms.
  • T and B cells are activated; seroconversion occurs within 4-10 weeks (antibodies may not appear for as long as 6 months, but ≥95% seroconvert within 6 months).
  • Reduction of HIV in the plasma is only partially controlled due to viral integration and downregulation of class I MHC molecules.
  • There is a rapid increase in viral load, followed by a decline as the immune system is activated.
  • CD4 T cell counts rapidly decline due to destruction and shift into secondary lymphatics, then rebound and stabilize.
  • Seroconversion marks the end of the acute HIV infection stage.
Clinical Latency

  • Patients are often asymptomatic or may present with persistent generalized lymphadenopathy.

  • Persistent infection and replication of HIV in infected cells cause a gradual decrease in CD4 T cells.

  • Macrophages and dendritic cells serve as reservoirs for HIV.

  • Activation of CD4 T cells increases viral infection and replication due to increased production of transcription factors.

  • The length of time patients are in clinical latency is highly variable.

  • The number of CD4 T cells gradually declines during clinical latency (avg. decline of 30-50 cells/µL per year), while HIV viral loads gradually increase due to T cell activation.

  • Eventually, T cell counts drop below a level for effective immune response, leading to patients becoming symptomatic, marking the end of the clinical latency period.

Early Symptomatic HIV Infection
  • Formerly known as AIDS-related complex (ARC).
  • More chronic symptoms of infection develop, including lymphadenopathy, weight loss, fever, malaise, and certain infections.
  • HIV induces cytopathologic effects (CPE) that can kill infected cells, including direct cell killing, syncytia formation, and apoptosis.
AIDS
  • Criteria for diagnosis:
    • HIV+ and at least one of the following:
      • A CD4 T cell count below 200 cells/µL.
      • A CD4 T cell percentage of <14% of total lymphocytes.
      • Presenting with an AIDS-defining opportunistic infection/malignancy.
  • Continued viral replication and destruction of T cells result in a decline in helper T cell function, subjecting patients to severe, overwhelming opportunistic infections.

HIV Antiretroviral Therapies

  • Five classes of FDA approved antiretrovirals are used in combination:
    • Nucleoside RT inhibitors (NRTIs)
    • Non-nucleoside RT inhibitors (NNRTIs)
    • Protease inhibitors
    • Entry/fusion inhibitors
    • Integrase inhibitors

Summary: General Information

  • Immunodeficiency = the absence, or failure of normal function, of one or more immune system components, resulting in increased susceptibility to infections.
    • Innate immunity defects → interference with phagocytosis and complement → increase in bacterial infections
    • B cell defects → decreased Igs → increase in pyogenic infections and enteric viruses/parasites
    • T cell defects → decreased CMI → increase in viral, intracellular organisms and most fungi
  • Often see decreased humoral immunity with T cell defects
  • Primary Immunodeficiencies = genetic (inherited) or developmental (congenital)
  • Secondary immunodeficiencies = acquired immunodeficiencies; causes: drugs, infection

Summary: HIV

  • Know the major events that occur during each stage of HIV infection:
    • Acute
    • Latency
    • Early symptomatic
    • AIDS