Y2S2 P2 Immunology Immunodeficiency
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Questions and Answers

What is the primary cause of primary immunodeficiencies?

  • Environmental factors
  • Nutritional deficiencies
  • Mutations to recessive genes (correct)
  • Acquired infections

    • What is a common feature of secondary immunodeficiencies?

  • Due to environmental factors (correct)
  • Genetic mutations present from birth
  • Always leads to T cell deficiency
  • Identified through family history

    • What consequence is associated with T cell deficiencies?

  • Enhanced antibody production
  • Increased risk of viral infections (correct)
  • Increase in pyogenic bacterial infections
  • Only mild respiratory infections

    • What characterizes Chronic Granulomatous Disease (CGD)?

    <p>Undue susceptibility to non-pathogenic organisms</p> Signup and view all the answers

    In Leukocyte Adhesion Deficiency (LAD), what is primarily affected?

    <p>Phagocyte extravasation</p> Signup and view all the answers

    What is a common clinical feature of Severe Combined Immunodeficiency (SCID)?

    <p>Almost completely lacking T cell immunity</p> Signup and view all the answers

    Which gene mutation is commonly associated with X-linked SCID?

    <p>Common cytokine gamma chain</p> Signup and view all the answers

    What is the treatment typically used for Chronic Granulomatous Disease?

    <p>Prophylactic antibiotics and stem cell transfer</p> Signup and view all the answers

    What is the role of NADPH oxidase in phagocytes?

    <p>To produce reactive oxygen species</p> Signup and view all the answers

    What is a notable clinical feature of LAD related to white blood cells?

    <p>High white blood cell count</p> Signup and view all the answers

    What is the primary function of RAG enzymes?

    <p>To recombine functional components of antibodies</p> Signup and view all the answers

    Which of the following is NOT a common outcome in patients with SCID?

    <p>Increased IgG synthesis</p> Signup and view all the answers

    What is a characteristic finding in patients with X-linked agammaglobulinemia?

    <p>Very high IgM and low levels of other immunoglobulins</p> Signup and view all the answers

    Which treatment is recommended for patients with severe immunodeficiencies?

    <p>Prophylactic antibiotics</p> Signup and view all the answers

    What is the impact of the Purine Salvage Pathway Enzymes deficiency?

    <p>No T cells or B cells present</p> Signup and view all the answers

    What is a consequence of lacking SAP in X-linked lymphoproliferative syndrome?

    <p>Inability to signal effectively from SLAM proteins</p> Signup and view all the answers

    Which symptom is commonly associated with patients suffering from SCID?

    <p>Opportunistic infections such as thrush</p> Signup and view all the answers

    What is the common treatment method for antibody deficiencies?

    <p>IV gamma-globulin and HSCT</p> Signup and view all the answers

    Which of the following terms is used to describe the condition with dysfunction in isotype switching?

    <p>Hyper-IgM syndrome</p> Signup and view all the answers

    What is the likely outcome for a person with untreated SCID?

    <p>Patients may die within a month</p> Signup and view all the answers

    What effect does a deficiency in RAG enzymes have on lymphocytes?

    <p>Lymphocytes are unable to produce antibodies.</p> Signup and view all the answers

    What is a notable characteristic of patients with X-linked agammaglobulinemia?

    <p>High levels of IgM but low levels of IgG, IgA, and IgE.</p> Signup and view all the answers

    What is one common outcome for patients with SCID after the initial months of life?

    <p>Development of severe opportunistic infections.</p> Signup and view all the answers

    In X-linked lymphoproliferative syndrome, what is a severe complication related to Epstein-Barr virus infection?

    <p>Inability to control the virus, leading to mononucleosis.</p> Signup and view all the answers

    What is one functional outcome of the Purine Salvage Pathway Enzymes deficiency?

    <p>Accumulation of toxic metabolites.</p> Signup and view all the answers

    What role do SAP and SLAM molecules play in T-cell activation?

    <p>They enhance killing of infected cells.</p> Signup and view all the answers

    Which treatment is essential for patients suffering from severe combined immunodeficiency (SCID)?

    <p>Prophylactic antibiotics.</p> Signup and view all the answers

    What characterizes dysgammaglobulinaemia seen in X-linked lymphoproliferative syndrome?

    <p>Impaired antibody responses.</p> Signup and view all the answers

    Which bacteria are commonly implicated in recurrent infections in patients with antibody deficiencies?

    <p>Escherichia coli.</p> Signup and view all the answers

    What is one potential finding in patients with X-linked agammaglobulinemia during immune response evaluation?

    <p>Absence of germinal centers.</p> Signup and view all the answers

    How do mutations that cause primary immunodeficiencies typically affect the immune system?

    <p>They cause different follow-on effects based on the specific gene affected.</p> Signup and view all the answers

    What is a common cause of secondary immunodeficiencies?

    <p>Environmental factors including infections and malnutrition.</p> Signup and view all the answers

    What role does CD18/beta2 integrin play in leukocyte adhesion?

    <p>Facilitates the binding of phagocytes to the site of infection.</p> Signup and view all the answers

    Which of the following clinical presentations is most associated with Chronic Granulomatous Disease?

    <p>Persistent bacterial and fungal infections.</p> Signup and view all the answers

    Which statement best describes the immune profile in Severe Combined Immunodeficiency (SCID)?

    <p>Marked deficiency in both T cells and NK cells with potentially normal B cells.</p> Signup and view all the answers

    What is a significant clinical outcome of leukocyte adhesion deficiency (LAD)?

    <p>Recurrent and severe bacterial infections.</p> Signup and view all the answers

    In the context of primary immunodeficiencies, which factor can lead to variability in clinical presentation among individuals with the same genetic mutation?

    <p>The expression level of the mutated gene.</p> Signup and view all the answers

    What specific aspect of the immune system is primarily impaired in patients suffering from X-linked SCID?

    <p>Cytokine signaling leading to T cell development.</p> Signup and view all the answers

    Which treatment modality is a common approach for managing Chronic Granulomatous Disease?

    <p>Prophylactic antibiotics and stem cell transplant.</p> Signup and view all the answers

    What is the major cause of the delayed healing and increased white blood cell count seen in LAD patients?

    <p>Impairment in the migration of phagocytes to sites of infection.</p> Signup and view all the answers

    Which statement best describes the nature of mutations causing primary immunodeficiencies?

    <p>Different mutations can affect different genes, leading to various immune vulnerabilities.</p> Signup and view all the answers

    What is the primary consequence of T cell deficiencies in immunodeficiency diseases?

    <p>Increased risk of viral and intracellular microbial infections.</p> Signup and view all the answers

    In Severe Combined Immunodeficiency (SCID), what is one of the main effects on lymphocyte levels?

    <p>A near-complete absence of lymphocytes in peripheral blood.</p> Signup and view all the answers

    Which mutation primarily leads to the symptoms experienced in Chronic Granulomatous Disease (CGD)?

    <p>Defects in the NADPH oxidase enzyme due to X-linked mutations.</p> Signup and view all the answers

    Which feature is commonly associated with Leukocyte Adhesion Deficiency (LAD)?

    <p>Inability of phagocytes to effectively migrate to infection sites.</p> Signup and view all the answers

    What is a common treatment approach for patients diagnosed with Severe Combined Immunodeficiency (SCID)?

    <p>Bone marrow transplantation to restore immune function.</p> Signup and view all the answers

    What type of infections are primarily associated with B cell deficiencies?

    <p>Frequent pyogenic bacterial infections.</p> Signup and view all the answers

    What is a notable clinical consequence of Chronic Granulomatous Disease (CGD)?

    <p>Development of granulation tissue in response to persistent infections.</p> Signup and view all the answers

    Which of the following genetic defects is most commonly responsible for X-linked SCID?

    <p>Deficiency of the common gamma chain of cytokine receptors.</p> Signup and view all the answers

    What is the impact of a deficiency in RAG enzymes on lymphocyte development?

    <p>Inability to produce isotype-switched antibodies</p> Signup and view all the answers

    Which of the following describes a significant outcome for patients with severe combined immunodeficiency (SCID)?

    <p>Early onset of severe opportunistic infections</p> Signup and view all the answers

    What is the primary defect seen in patients with X-linked agammaglobulinemia?

    <p>Failure of B cells to differentiate into plasma cells</p> Signup and view all the answers

    Which of the following treatments is critical for managing X-linked lymphoproliferative syndrome?

    <p>Stem cell transplantation</p> Signup and view all the answers

    Which component of the immune response is primarily affected by a deficiency in the Purine Salvage Pathway Enzymes?

    <p>Mature T cells and NK cells</p> Signup and view all the answers

    What is one of the consequences of impaired isotype switching in X-linked agammaglobulinemia?

    <p>Inability to activate complement via antibodies</p> Signup and view all the answers

    In the context of T-cell activation, what role does SAP play?

    <p>Binding to phosphotyrosine residues for signal transduction</p> Signup and view all the answers

    Which outcome is most commonly observed in patients with X-linked lymphoproliferative syndrome?

    <p>Development of lymphomas and dysgammaglobulinemia</p> Signup and view all the answers

    How does IgM contribute to immunity in patients with defects in antibody production?

    <p>It activates complement pathways efficiently without isotype switching</p> Signup and view all the answers

    What is a characteristic feature of patients suffering from intractable diarrhea due to viral infections?

    <p>It typically accompanies nutritional deficiencies</p> Signup and view all the answers

    What is the primary immunological consequence of Chronic Granulomatous Disease (CGD)?

    <p>Inability to produce reactive oxygen species</p> Signup and view all the answers

    Which aspect of immune function is directly affected by Leukocyte Adhesion Deficiency (LAD)?

    <p>Migration of phagocytes to sites of infection</p> Signup and view all the answers

    What type of pathogens are primarily responsible for infections in patients with B cell deficiencies?

    <p>Pyogenic bacterial infections</p> Signup and view all the answers

    What is the clinical significance of varying effects seen from mutations in the same gene in primary immunodeficiencies?

    <p>They may result in different immune system vulnerabilities</p> Signup and view all the answers

    Which condition is correctly associated with an autosomal recessive inheritance pattern?

    <p>Leukocyte Adhesion Deficiency (LAD)</p> Signup and view all the answers

    In Severe Combined Immunodeficiency (SCID), what is affected in addition to T cell development?

    <p>B cell effector functions</p> Signup and view all the answers

    What role do reactive oxygen species play in the immune response of phagocytes?

    <p>They aid in killing of engulfed pathogens</p> Signup and view all the answers

    What is a common clinical presentation in severe cases of Leukocyte Adhesion Deficiency (LAD)?

    <p>Persistent gingivitis and skin infections</p> Signup and view all the answers

    What is the underlying defect in the most common type of SCID?

    <p>Mutation of cytokine receptors</p> Signup and view all the answers

    What is the primary reasoning behind the absence of T cells and B cells in conditions caused by RAG enzyme deficiencies?

    <p>Failure in receptor expression for positive selection</p> Signup and view all the answers

    In the context of X-linked agammaglobulinemia, what is primarily affected by the defect in isotype switching?

    <p>Production of IgM only</p> Signup and view all the answers

    Which of the following best describes the role of SAP in the context of T-cell activation?

    <p>Aids in signal transduction involving tyrosine residues</p> Signup and view all the answers

    What is the significance of maternal antibodies in the context of SCID during the first few months of life?

    <p>They offer temporary protection until severe infections develop.</p> Signup and view all the answers

    What is the expected immune profile in patients with X-linked lymphoproliferative syndrome?

    <p>Dysgammaglobulinaemia leading to hypogammaglobulinaemia</p> Signup and view all the answers

    What treatment is considered essential for patients with severe combined immunodeficiency (SCID) to prevent mortality?

    <p>Intravenous immunoglobulins</p> Signup and view all the answers

    In the management of X-linked agammaglobulinemia, which of the following is a key therapeutic approach?

    <p>IV gamma-globulin therapy</p> Signup and view all the answers

    What is a common complication associated with a deficiency in the Purine Salvage Pathway Enzymes?

    <p>Accumulation of toxic metabolites leading to immune dysfunction</p> Signup and view all the answers

    In patients with SCID, what type of infections are predominantly observed later in life?

    <p>Opportunistic viral infections</p> Signup and view all the answers

    What lymphocyte population observation is characteristic in patients suffering from X-linked agammaglobulinemia?

    <p>Absence of plasma cells</p> Signup and view all the answers

    Study Notes

    Primary Immunodeficiencies

    • Rare congenital diseases
    • Manifest early in life
    • Characterized by repeated infections, often with the same or similar pathogens
    • Caused by mutations to recessive genes (commonly X-linked)
    • Mutations affect different genes that encode different molecules, leading to varying effects on the immune system
    • Mutations in the same gene can have varying effects (point mutation, frameshift mutation, promoter region mutations)
    • Example: IgA deficiency (25% have poor mucosal immunity, 75% are asymptomatic)

    Secondary Immunodeficiencies

    • Acquired later in life from environmental factors
    • Examples: infections (HIV, measles, malaria), malnutrition, cancer, medical treatments (chemotherapy, radiotherapy, immunosuppressive drugs)

    General Features of Immunodeficiency Diseases

    • B cell deficiencies: Consequences include pyogenic bacterial infections
    • T cell deficiencies: Consequences include viral and other intracellular microbial infections, and virus-associated malignancies
    • Innate immune deficiencies: Consequences are variable, but an increase in pyogenic bacterial infections is common

    Chronic Granulomatous Disease (CGD)

    • Undue susceptibility to persistent bacterial and fungal infections in the first two years of life
    • Organisms are often non-pathogenic
    • Infections heal slowly, forming granulomas (intracellular pathogens cannot be eliminated, infecting macrophages, fused macrophages, and Th1 cells)
    • Causes pneumonia, lymphadenitis, skin abscesses, and visceral infection
    • Treatment includes prophylactic antibiotics, anti-inflammatories, and hematopoietic stem cell transfer
    • Normally, phagocytes use reactive oxygen species to eliminate bacteria, produced by phagocyte oxidase
    • In CGD, the enzyme NADPH oxidase (produces superoxide ions) is mutated on the X chromosome

    Leukocyte Adhesion Deficiency (LAD)

    • Autosomal recessive condition
    • Phagocytes can function but cannot access the site of infection
    • Macrophages utilize selectins and integrins to extravasate
    • In LAD, there is a defect in the CD18/beta2 integrin (also impacts phagocytosis, as Mac1 is a complement receptor)
    • Rarer form has a selectin defect
    • Causes severe recurrent bacterial infections (from genuine, not opportunistic pathogens)
    • Treatment involves prophylactic antibiotics and bone marrow transplants
    • Common symptoms: severe gingivitis, high white blood cell count, normal antibody responses, delayed wound healing

    Severe Combined Immunodeficiency (SCID)

    • Series of genetic defects affecting the development of T cells, and sometimes B cells and NK cells
    • Presents with few lymphocytes in the periphery and almost completely lacking T cell based immunity and T cell antibody response
    • Affects thymic development, disrupting the medulla and cortex, impacting cell maturation

    SCID Genetic Causes

    • X-linked SCID: common cytokine gamma chain receptor deficiency; no T cells or NK cells; normal B cell counts (common gamma chains have a signaling role, lack of signaling prevents phosphorylation, especially towards IL-7, which promotes development)
    • RAG (recombination activating genes)-1/2 enzymes (autosomal): No T cells or B cells; RAG is an enzyme that recombines functional components of antibodies; without it, lymphocytes cannot express receptors for positive selection
    • Purine Salvage Pathway Enzymes (autosomal): No T cells, B cells, or NK cells; these enzymes catabolize nucleic acids; deficiency leads to an accumulation of toxic metabolites

    SCID Outcomes and Treatment

    • Outcomes:
      • Patients survive the first few months due to maternal antibodies, then develop severe opportunistic infections (often thrush)
      • Commonly have coughs or pneumonia from viral infections
      • Intractable diarrhea from viruses or E. coli
    • Treatment:
      • Prophylactic antibiotics
      • Intravenous immunoglobulins
      • Hygiene measures
      • Avoidance of live attenuated vaccines
      • Without treatment, patients often die within a month

    Antibody Deficiencies

    • X-linked agammaglobulinemia with hyper-IgM
    • High IgM, low or absent IgG, IgA, and IgE
    • Defect in isotype switching (can only make IgM)
      • Isotype switching occurs in germinal centers, driven by cytokines and CD40L:CD40 (CD40 is the X-linked mutation)
    • Limited immunity, as IgM is good at activating complement but not at neutralizing toxins or opsonization
    • Plasma cells exist, but germinal centers (indicative of a good B cell response) are lacking
    • Normal blood lymphocytes but may have neutropenia
    • Recurrent pyogenic bacterial infections and susceptibility to some opportunistic pathogens
    • Treatment: IV gamma-globulin, prophylactic antibody, HSCT

    Defects in T Cell Activation

    • X-linked lymphoproliferative syndrome
    • Phenotypes:
      • Fulminating infectious mononucleosis (inability to control Epstein Barr virus infection)
      • B cell lymphomas and/or lymphoproliferation
      • Dysgammaglobulinemia progressing to hypogammaglobulinemia
    • Related to SAP and SLAM molecules
      • SAP plays a role in signal transduction
      • SLAM proteins expressed on leukocytes via tyrosine residues
      • SLAM and SAP on NK and CTL cells
        • Enhance killing of infected cells (infected B cells or transformed lymphoma cells)
      • Without SAP, SLAM cannot signal, inhibiting killing of infected cells

    Primary Immunodeficiency

    • Rare congenital diseases that present early in life, characterized by recurring infections
    • Caused by recessive gene mutations (often X-linked)
      • Mutations affect different genes, resulting in diverse vulnerabilities within the immune system
      • Mutations in the same gene can have varying effects, with point mutations having a lesser effect than frameshift mutations
    • Example of a primary immunodeficiency is IgA deficiency, with 75% of cases showing near-asymptomatic presence while 25% have poor mucosal immunity

    Secondary Immunodeficiency

    • Acquired later in life due to environmental factors such as:
      • Infections (HIV, measles, malaria)
      • Malnutrition (causing T cell deficiency)
      • Cancer
      • Medical treatments (chemotherapy, radiotherapy, immunosuppressive drugs)

    General Features of Immunodeficiency Diseases

    • B cell deficiencies:
      • Result in pyogenic bacterial infections
    • T cell deficiencies:
      • Result in viral/intracellular microbial infections and virus-associated malignancies
    • Innate immune deficiencies:
      • Result in increased susceptibility to pyogenic bacterial infections

    Chronic Granulomatous Disease (CGD)

    • Characterized by persistent bacterial/fungal infections in the first two years of life
    • Caused by mutations in the NADPH oxidase gene on the X chromosome
    • Leads to an inability to produce reactive oxygen species (ROS) needed for phagocytosis
    • Presents with pneumonia, lymphadenitis, skin abscesses, and visceral infections
    • Treatment involves prophylactic antibiotics, anti-inflammatories, and hematopoietic stem cell transfer

    Leukocyte Adhesion Deficiency (LAD)

    • Autosomal recessive condition characterized by phagocytes with functional limitations
    • Defects in the CD18/beta2 integrin or selectins prevent phagocytes from reaching infection sites
    • Results in severe recurrent bacterial infections
    • Common presentations include severe gingivitis, high white blood cell count, normal antibody responses, and delayed wound healing
    • Treatment includes prophylactic antibiotics and bone marrow transplants

    Severe Combined Immunodeficiency (SCID)

    • A group of genetic defects affecting the development of T cells and often B cells and NK cells
    • Leads to a lack of T cell-mediated immunity and antibody response
    • Three main genetic causes:
      • X-linked SCID: mutation in the common cytokine gamma chain receptor, impacting T cell and NK cell development
      • RAG-1/2 deficiency: mutation blocks recombination of antibody components, affecting T and B cell development
      • Purine salvage pathway enzyme deficiency: disrupts nucleic acid metabolism, leading to toxic metabolite accumulation, affecting T, B, and NK cell development
    • SCID patients often present with severe opportunistic infections, including thrush
    • Treatment includes prophylactic antibiotics, intravenous immunoglobulins, hygiene measures, and avoidance of live attenuated vaccines

    Antibody Deficiencies

    • X-linked agammaglobulinemia with hyper-IgM
    • Characterized by high IgM levels and low/absent IgG, IgA, and IgE
    • Defect in immunoglobulin isotype switching, resulting in limited immunity
    • Germinal centers are absent, indicating a poor B cell response
    • Frequent pyogenic bacterial infections and susceptibility to opportunistic pathogens
    • Treatment includes IV gamma-globulin, prophylactic antibodies, and hematopoietic stem cell transplantation

    Defects in T-Cell Activation

    • X-linked lymphoproliferative syndrome (XLP)
    • Three phenotypes:
      • Fulminating infectious mononucleosis, due to inability to control Epstein-Barr virus infection
      • B cell lymphomas and/or lymphoproliferation
      • Dysgammaglobulinemia, which can progress into hypogammaglobulinemia
    • Related to SAP and SLAM molecules, both involved in signal transduction
    • Defects in SAP prevent SLAM signaling, impairing NK and CTL cell activation and infected cell killing

    Primary Immunodeficiencies

    • Rare, congenital illnesses that appear early in life
    • Characterized by recurrent infections, often with the same or similar pathogens (frequently opportunistic)
    • Caused by mutations to recessive genes, commonly X-linked
    • Clinical effects vary due to:
      • Mutations affecting different genes encoding different molecules, impacting the immune system in various ways
      • Mutations to the same gene can have diverse effects (point mutation, frameshift mutation, promoter region mutations)
    • Example: In IgA deficiency, 25% of individuals have poor mucosal immunity, while 75% are almost asymptomatic.

    Secondary Immunodeficiencies

    • Acquired later in life due to environmental factors including:
      • Infections: HIV, measles, malaria
      • Malnutrition: leading to T cell deficiency
      • Cancer
      • Medical treatments: chemotherapy, radiotherapy, immunosuppressive drugs

    General Features of Immunodeficiency Diseases

    • B cell deficiencies: Result in pyogenic bacterial infections
    • T cell deficiencies: Lead to viral and other intracellular microbial infections, and virus-associated malignancies
    • Innate immune deficiencies: Consequences vary, but often include an increase in pyogenic bacterial infections

    Chronic Granulomatous Disease (CGD)

    • Characterized by increased susceptibility to persistent bacterial and fungal infections in the first two years of life
    • Affected individuals experience slow-healing infections that form granulomas
    • Granulomas occur when an intracellular pathogen cannot be eliminated and infects macrophages, fused macrophages, and Th1 cells
    • Commonly causes pneumonia, lymphadenitis, skin abscesses, and visceral infections
    • Treated with prophylactic antibiotics, anti-inflammatories, and hematopoietic stem cell transfer
    • Phagocytes (including monocytes) normally combat bacteria using reactive oxygen species (ROS) produced by phagocyte oxidase
    • In CGD, the NADPH oxidase enzyme (responsible for producing superoxide ions) is mutated on the X chromosome

    Leukocyte Adhesion Deficiency (LAD)

    • An autosomal recessive disorder where phagocytes can function but struggle to reach infection sites
    • Normally, macrophages utilize selectins to slow down and integrins to bind strongly, enabling extravasation
    • In LAD:
      • There's a defect in the CD18/beta2 integrin (which also impacts phagocytosis as Mac1 is a complement receptor)
      • A rarer form has a selectin defect
    • Results in severe recurrent bacterial infections (often from genuine rather than opportunistic pathogens) that can be fatal if left untreated
    • Treated with prophylactic antibiotics and bone marrow transplants
    • Common presentations include severe gingivitis, high white blood cell count, normal antibody responses, and delayed wound healing

    Severe Combined Immunodeficiency (SCID)

    • A group of genetic defects affecting the development of T cells, and sometimes B cells and NK cells
    • Characterized by low lymphocyte counts in the periphery, nearly absent T cell-based immunity, and impaired T cell antibody response
    • Affects thymic development, disrupting the medulla and cortex, impacting cell maturation
    • Three major genetic causes:
      • X-linked SCID: Common cytokine gamma chain receptor deficiency:
        • No T cells or NK cells, normal B cell counts
        • Common gamma chains (2, 4, and 7) have signaling roles, but a deficiency prevents signaling and phosphorylation, particularly towards IL-7 (crucial for development)
      • RAG (recombination activating genes)-1/2 enzymes:
        • No T cells or B cells
        • RAG enzymes recombine functional antibody components. Without them, lymphocytes cannot express receptors for positive selection
      • Purine Salvage Pathway Enzymes:
        • No T cells, B cells, or NK cells
        • These enzymes catabolize nucleic acids. A deficiency leads to toxic metabolite accumulation

    SCID Outcomes and Treatment

    • Outcomes:
      • Patients survive the first few months due to maternal antibody protection, but then develop severe opportunistic infections (often thrush)
      • Common symptoms include coughs, pneumonia from viral infections, and intractable diarrhea from viruses or E.coli
    • Treatment:
      • Prophylactic antibiotics
      • Intravenous immunoglobulins
      • Hygiene measures
      • Avoidance of live attenuated vaccines
      • Without treatment, patients usually die within a month

    Antibody Deficiencies

    • X-linked agammaglobulinemia with hyper-IgM
      • High IgM levels, low or absent IgG, IgA, and IgE
      • Defective isotype switching (IgM is produced, but not other antibody classes)
        • Switching is isotype-dependent, occurs in germinal centers, driven by cytokines and CD40L:CD40 (CD40 is the X-linked mutation)
      • IgM has limited immunity (good at activating complement but not at neutralizing toxins or opsonization)
      • Plasma cells exist, but germinal centers are absent
    • Normal blood lymphocytes but neutropenia may occur
    • Recurrent pyogenic bacterial infections and some susceptibility to opportunistic pathogens
    • Treatment: IV gamma-globulin, prophylactic antibodies, HSCT

    Defects in T-Cell Activation

    • X-linked lymphoproliferative syndrome
      • Three phenotypes:
        • Fulminating infectious mononucleosis: Difficulty controlling Epstein Barr virus infection
        • B cell lymphomas and/or lymphoproliferation
        • Dysgammaglobulinaemia that can progress to hypogammaglobulinemia
    • Related to SAP and SLAM molecules
      • SAP promotes signal transduction by binding to phosphotyrosine residues
        • A family of SLAM proteins on leukocytes express via tyrosine residues
        • SLAM and SAP are expressed on NK and CTL cells
      • Normally, these molecules signal, enhancing infected cell killing (infected B cells or transformed B cell lymphomas). Without SAP, SLAM cannot signal

    Primary Immunodeficiencies

    • Rare, congenital diseases that manifest early in life.
    • Characterized by repeated infections, often with the same or similar pathogens (often opportunistic).
    • Caused by mutations to recessive genes (commonly X-linked).
    • Clinical effects vary because mutations affect different genes, impacting different parts of the immune system.
    • Mutations in the same gene can have varying effects (point mutations: slight effect, frameshift mutations: shortened or abolished proteins, promoter region mutations: altered expression).
    • Example: In IgA deficiency, 25% of people have poor mucosal immunity, while 75% are nearly asymptomatic.

    Secondary Immunodeficiencies

    • Acquired later in life from environmental factors.
    • Examples include: infections (HIV, measles, malaria), malnutrition (causing T cell deficiency), cancer, and medical treatments (chemotherapy, radiotherapy, and immunosuppressive drugs).

    General Features of Immunodeficiency Diseases

    • B cell deficiencies: consequences include pyogenic bacterial infections.
    • T cell deficiencies: consequences include viral and other intracellular microbial infections, and virus-associated malignancies.
    • Innate immune deficiencies: consequences are variable but often include an increase in pyogenic bacterial infections

    Chronic Granulomatous Disease (CGD)

    • Characterized by susceptibility to persistent bacterial and fungal infections in the first two years of life, caused by organisms normally non-pathogenic.
    • Infections heal slowly, forming granulomas which occur when an intracellular pathogen cannot be eliminated and infects macrophages, fused macrophages, and Th1 cells.
    • Symptoms include pneumonia, lymphadenitis, skin abscesses, and visceral infection.
    • Treatment includes prophylactic antibiotics, anti-inflammatories, and hematopoietic stem cell transfer.
    • CGD is caused by mutations to the NADPH oxidase gene on the X chromosome.
    • Normally, phagocytes (and monocytes) produce reactive oxygen species (ROS) through phagocyte oxidase.
    • NADPH oxidase produces superoxide ions.

    Leukocyte Adhesion Deficiency (LAD)

    • Autosomal recessive condition.
    • Phagocytes can function but cannot access the site of infection.
    • Macrophages normally have selectins, which slow the cell down, and integrins, which bind strongly to allow extravasation.
    • Defect in the CD18/beta2 integrin (phagocytosis is also impacted as Mac1 is a complement receptor).
    • A rarer type of LAD exists due to a defect in selectin instead.
    • Causes severe recurrent bacterial infections (usually from genuine rather than opportunistic pathogens), which can be fatal if untreated.
    • Treatment includes prophylactic antibiotics and bone marrow transplants.
    • Other symptoms include severe gingivitis, high white blood cell count, normal antibody responses, and delayed wound healing.

    Severe Combined Immunodeficiency (SCID)

    • Series of genetic defects affecting T cell development (sometimes B cells and NK cells too).
    • Presents with few lymphocytes in the periphery, almost completely lacking T cell-based immunity and T cell antibody response.
    • Affects thymic development, disrupting the medulla and cortex, impacting cell maturation.

    SCID Genetic Causes

    • X-linked SCID (common cytokine gamma chain receptor deficiency): no T cells or NK cells, B cells have normal numbers.

      • Common gamma chains (2, 4, and 7) have a signaling role, but without them, the receptors do not signal, preventing phosphorylation, particularly towards IL-7 (which promotes development).

    • RAG (recombination activating genes)-1/2 enzymes (autosomal): no T cells or B cells.

      • RAG enzymes recombine the functional components of antibodies.
      • Without RAG, lymphocytes cannot express receptors needed for positive selection.

    • Purine Salvage Pathway Enzymes (autosomal): no T cells, B cells, or NK cells.

      • These enzymes normally catabolize nucleic acids.
      • Deficiency leads to an accumulation of toxic metabolites.

    SCID Outcomes and Treatment

    • Outcomes: patients survive the first few months due to maternal antibodies, but then develop severe opportunistic infections (usually oral thrush or nappy area first).

      • Common symptoms include cough or pneumonia from viral infections, and intractable diarrhea from viruses or E.coli.

    • Treatment: prophylactic antibiotics, intravenous immunoglobulins, hygiene measures, avoidance of live-attenuated vaccines.

      • Without treatment, patients die within a month.

    Antibody Deficiencies

    • X-linked agammaglobulinemia with hyper-IgM: very high IgM and low or absent IgG, IgA, and IgE.
      • This is a defect in isotype switching, meaning only IgM is produced.
        • Isotype switching is isotype-dependent, occurring in germinal centers, driven by cytokines and CD40L:CD40 (CD40 is the X-linked mutation).
      • Despite the presence of IgM, which is good at activating complement, there is limited immunity as IgM is not effective at neutralizing toxins or opsonization.
      • Plasma cells exist, but germinal centers are lacking.
      • Normal blood lymphocytes, but neutropenia can occur.
      • Recurrent pyogenic bacterial infections and susceptibility to opportunistic pathogens.
    • Treatment: IV gamma-globulin, prophylactic antibody, HSCT.

    Defects in T-Cell Activation

    • X-linked lymphoproliferative syndrome: three phenotypes:
      • Fulminating infectious mononucleosis (inability to control Epstein Barr virus infection).
      • B cell lymphomas and/or lymphoproliferation.
      • Dysgammaglobulinemia, which can progress into hypogammaglobulinemia.
    • SAP and SLAM molecules are involved.
      • SAP binds to phosphotyrosine residues, playing a role in signal transduction.
      • SLAM proteins are expressed on leukocytes via tyrosine residues.
      • SLAM and SAP are expressed on NK and CTL cells, enhancing the killing of infected cells (infected B cell or transformed B cell lymphoma).
      • Without SAP, SLAM cannot signal.

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