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Questions and Answers
What is the primary role of T-cells in the immune system?
Which type of infection is a significant indicator of potential immunodeficiency?
What is the initial immunoglobulin produced by B-cells?
Why might the diagnosis of immunodeficiency be challenging?
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What characteristic is associated with neutrophils and macrophages in the immune response?
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What is the primary defect in white blood cells associated with the inability to produce activated oxygen compounds?
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Which of the following pathogens is most commonly associated with recurrent abscesses in patients with immune deficiencies?
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In patients with impaired lysis of phagocytized bacteria, which clinical finding is NOT typical?
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What diagnostic method has replaced the NBT test for measuring oxidant production in certain immune deficiencies?
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Which of the following conditions is characterized by recurrent infections and giant granules in neutrophils?
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What is the only definitive treatment for certain immune deficiencies mentioned?
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Patients with T-cell deficiencies are particularly vulnerable to infections from which type of organism?
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Which of the following is NOT a common treatment strategy for patients with recurrent infections due to immune deficiencies?
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What is the primary defining characteristic of vasculitis?
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Which of the following symptoms may indicate the presence of vasculitis?
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Which type of vasculitis is characterized by IgA deposits in small blood vessels?
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What is a possible consequence of necrotizing inflammation in vasculitis?
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Which type of vasculitis is classified as a medium vessel vasculitis?
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Which feature is NOT typically associated with vasculitis?
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What distinguishes primary from secondary vasculitis?
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In which group does Takayasu's arteritis belong?
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What is the primary treatment for severe antibody disorders?
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What significant caution should be taken when administering blood products for patients with selective IGA deficiency?
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Which of the following is NOT a treatment option for cellular deficiency?
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Common Variable Immunodeficiency (CVID) is characterized by which of the following?
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What is a common clinical finding in patients with X-linked agammaglobulinemia?
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Which of the following best describes the infections associated with X-linked agammaglobulinemia?
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Which of the following is a notable side effect of combined immune deficiency disorders treated with blood transfusions?
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What distinguishes common variable immunodeficiency from X-linked agammaglobulinemia in terms of lymphoid tissue?
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Which primary immunodeficiency is associated with failure to thrive in newborns and young infants?
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What does a normal Absolute Neutrophil Count rule out in a patient suspected of having neutropenia?
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Which condition is diagnosed primarily through measurement of Immunoglobulin A (IgA) levels?
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Which of the following is most associated with predominantly antibody deficiencies?
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What screening test would be used to assess for complement deficiencies?
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Which of the following conditions is characterized by recurrent respiratory tract infections and poor growth?
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At what age are children typically screened for X-linked agammaglobulinemia?
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Which condition is least likely to present with lymphadenopathy?
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Which feature is characteristic of diseases of immune dysregulation?
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What is a common clinical feature of complement deficiencies?
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Study Notes
Lymphoid Progenitors
- Lymphoid progenitors differentiate into T-cells in the thymus, essential for cellular immunity.
- T-cells develop into CD4, CD8, or other cells, and release cytokines and interleukins that assist B-cells in forming antibodies.
- Lymphoid progenitors also differentiate into B-cells in the bone marrow.
- B-cells begin with IgM and mature to produce IgA, IgE, or IgG (subclasses 1-4), ultimately becoming plasma cells.
- Plasma cells are responsible for producing antibodies, which surround antigens for phagocytosis and mediate specific immunity and memory.
Neutrophils and Macrophages
- Neutrophils and macrophages are phagocytic cells that engulf and destroy organisms, often those covered by antibodies.
- This process is known as phagocytosis and opsonization.
- They contribute to natural or innate immunity, a nonspecific defense mechanism.
Complement System
- The complement system is a cascade of plasma proteins that aids in chemotaxis (attracting immune cells) and opsonization (marking targets for phagocytosis).
Suspecting Immunodeficiency
- Suspect immunodeficiency in cases of unusual, chronic, or recurrent infections including:
- At least one systemic bacterial infection (sepsis, meningitis).
- At least two serious respiratory or bacterial infections (cellulitis, abscesses, otitis media, pneumonia) within a year.
- Serious infections at unusual sites (liver, brain abscesses).
- Infections with unusual pathogens.
- Infection with common childhood pathogens but of unusual severity.
- Family history of early infant death or a known immunodeficiency disorder.
- Additional clues may include failure to thrive with or without chronic diarrhea, persistent infections after receiving live vaccines, and chronic oral or cutaneous candidiasis.
Diagnosis Challenges
- Immunodeficiency diseases are not routinely screened for, making diagnosis difficult.
- Extensive antibiotic use may mask the typical presentation of immunodeficiency.
Complement Deficiencies
- Complement deficiencies can involve any age group.
- They can lead to infections by bacteria like pneumococci and Neisseria, affecting various organs like the meninges, joints, and leading to septicemia, recurrent sinopulmonary infections, and arthritis.
- They can also result in autoimmune disorders such as systemic lupus erythematosus (SLE), vasculitis, scleroderma, dermatomyositis, and glomerulonephritis.
Primary Immunodeficiency Disease Categories
- The International Union of Immunological Societies (IUIS) classification system categorizes primary immunodeficiencies into ten groups:
- I: Immunodeficiencies affecting cellular and humoral immunity
- II: Combined immunodeficiencies with associated or syndromic features
- III: Predominantly antibody deficiencies
- IV: Diseases of immune dysregulation
- V: Congenital defects of phagocyte number or function
- VI: Defects in intrinsic or innate immunity
- VII: Autoinflammatory disorders
- VIII: Complement deficiencies
- IX: Bone marrow failure
- X: Phenocopies of inherited errors of immunity
Common Features of Primary Immunodeficiencies
- Common clinical features include recurrent respiratory tract infections, severe bacterial infections, persistent infections with incomplete response, persistent sinusitis or mastoiditis, failure to thrive/growth retardation, and diarrhea or malabsorption.
- Less common features include lymphadenopathy, hepatosplenomegaly, recurrent meningitis, pyoderma, and deep infections like osteomyelitis and cellulitis.
Age at Presentation of Primary Immunodeficiencies
- Newborn and young infants (0-6 months): SCID, LAD, DiGeorge anomaly, Wiskott-Aldrich syndrome, X-linked hyper IgM syndrome
- Infants and young children (6 months - 5 years): CGD, Hyper IgE syndrome, Chediak-Higashi syndrome, Chronic mucocutaneous candidiasis, X-linked lymphoproliferative syndrome
- Older children (>5 years) and adults: X-linked agammaglobulinemia, Ataxia telangiectasia, Common variable immunodeficiency
Screening Tests for Immunodeficiency
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CBC with DLC & ESR (Hemogram):
- Normal absolute neutrophil count rules out congenital or acquired neutropenia and leucocyte adhesion defect (LAD).
- Normal absolute lymphocyte count rules out T-cell defects.
- Normal platelet count rules out Wiskott-Aldrich syndrome (WAS).
- Normal ESR makes chronic bacterial or fungal infection unlikely.
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Screening for T-cell defects:
- Normal absolute lymphocyte count rules out T-cell defects.
- Flow cytometry: assess for naive T-cells (CD3+CD45RA).
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Screening for B-cell defects:
- Evaluate IgA levels, and if abnormal, measure IgM and IgG.
- Assess antibody titres to protein and polysaccharide antigens (e.g., isohemagglutinins, anti-blood group substances, vaccine antigens).
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Screening for phagocytic cell disorders:
- Measure absolute neutrophil count.
- Perform a respiratory burst assay.
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Screening for complement deficiencies:
- CH50 test: measures the integrity of the entire complement pathway. Low values suggest a deficiency.
Management of Primary Immunodeficiencies
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General Management:
- Diet modifications.
- Avoidance of pathogens (germ-free care).
- Antibiotic therapy.
- Avoidance of whole blood transfusions in combined immune deficiency disorders (risk of graft-versus-host reaction).
- Avoidance of live virus vaccines and BCG.
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Immunoglobulin Replacement:
- Treatment of severe antibody disorders:
- IVIG: 400-600 mg/kg/m
- Frozen plasma: 10 ml/kg/m
- Caution with blood product administration in selective IgA deficiency.
- Treatment of severe antibody disorders:
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Specific treatment of cellular deficiency:
- Bone marrow transplantation.
- Replacement therapy:
- Enzyme replacement.
- Gene therapy.
- Thymic hormone administration.
- Cytokine therapy.
- Fetal thymus transplantation.
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Specific treatment of phagocytic disorders:
- Interferon gamma for chronic granulomatous disease (CGD).
- Granulocyte transfusions.
X-Linked (Bruton) Agammaglobulinemia
- This is a profound defect in B-cell development, resulting in an absence of circulating B-cells and severe hypogammaglobulinemia.
- It causes small or absent tonsils and no palpable lymph nodes.
- Caused by mutations in the BTK gene on the X chromosome, which encodes Bruton tyrosine kinase, vital for B-cell development and maturation.
- Clinical findings: Boys with pyogenic sinopulmonary infections, recurrent infections with encapsulated bacteria.
- Diagnosis: Based on clinical presentation, lymphoid hypoplasia, severely depressed immunoglobulins, absent B-cells on flow cytometry, and gene sequencing.
- Treatment: Antibiotics and regular monthly IVIG.
Common Variable Immunodeficiency (CVID)
- Defined by hypogammaglobulinemia with phenotypically normal B-cells, but blood B-lymphocytes are unable to differentiate into antibody-producing cells.
- Affects both boys and girls equally, with later onset and less severe infections compared to X-linked agammaglobulinemia.
- Diagnosis: Clinical presentation, low or severely depressed serum immunoglobulins, normal-sized lymphoid tissue, and later development of autoimmune disease and malignancy (lymphoma).
- Treatment: Similar to X-linked agammaglobulinemia, including antibiotics and regular monthly IVIG, but more complex due to variable disease severity.
Chronic Granulomatous Disease (CGD)
- Deficient NADPH oxidase activity leads to impaired production of hydrogen peroxide, superoxide, and other activated oxygen compounds in white blood cells (WBCs).
- Phagocytic function is severely impaired.
- Clinical findings: Variable age of onset and severity, recurrent abscesses (skin, lymph nodes, liver), pneumonia, osteomyelitis, commonly caused by S. aureus, Aspergillus, C. albicans, Nocardia, and Salmonella.
- Granuloma formation is a distinctive feature, due to the accumulation of undigested material, and can cause complications like pyloric outlet obstruction, bladder or ureteral obstruction, rectal fistulae, or granulomatous colitis.
- Diagnosis: Flow cytometry with dihydrorhodamine 123 (DHR) measures oxidant production, replacing the nitroblue tetrazolium (NBT) test.
- Treatment: Stem cell transplantation is the cure, otherwise supportive care including interferon gamma therapy to reduce serious infections.
Chediak-Higashi Syndrome
- Impaired lysis of phagocytized bacteria, leading to recurrent bacterial infections.
- Genetics: Autosomal recessive disorder.
- Clinical findings: Recurrent infections, oculocutaneous albinism, hepatosplenomegaly, lymphadenopathy, pancytopenia, bleeding diathesis, and neurologic changes.
- Diagnosis: Neutropenia and giant granules in neutrophils. Genetic testing for LYST mutations confirms the diagnosis.
Evaluation of Suspected Immune Deficiency
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Organisms Commonly Associated with B-Cell Deficiency:
- Recurrent bacterial infections: Streptococci, Staphylococci, Haemophilus, Campylobacter
- Viral: Enteroviruses
- Uncommon: Giardia, Cryptosporidia
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Organisms Commonly Associated with T-Cell Deficiency:
- Opportunistic organisms: CMV, EBV, varicella, Candida, Pneumocystis jiroveci, mycobacteria
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Organisms Commonly Associated with Complement Deficiency:
- Pneumococci, Neisseria
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Organisms Commonly Associated with Neutrophil Deficiency:
- Bacteria: Staphylococci, Pseudomonas, Serratia, Klebsiella, Salmonella
- Fungi: Candida, Aspergillus
Vasculitis
- Inflammation of blood vessels that can lead to thickening, stenosis, occlusion, ischemia, necrosis, and bleeding.
- May involve any vessel and any organ system.
- Clinical presentation varies based on the type of inflammation, size, and distribution of the involved blood vessels.
Suspecting Vasculitis
- Suspect vasculitis in unexplained systemic illness (no sepsis, malignancy, or drug-related causes), multiple organ involvement with no obvious cause, symptoms of organ ischemia, and suggestive features like palpable purpura, glomerulonephritis (hematuria), mononeuritis multiplex, and lung infiltrates.
Vasculitis Classification
- Primary vs. Secondary: Primary vasculitis has no known underlying cause, while secondary vasculitis is associated with another condition.
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Size of involved vessels:
- Large: Giant cell (temporal) arteritis (GCA) / Takayasu's arteritis
- Medium: Polyarteritis Nodosa (PAN) / Kawasaki's disease
- Small and Medium: Wegener's granulomatosis / Churg-Strauss syndrome / Microscopic polyangiitis
- Small: Henoch-Schönlein Purpura (HSP) / Essential mixed cryoglobulinemia
- ANCA (Anti-Neutrophil Cytoplasmic Antibody) Positive or Negative: Identifies a specific type of antibody that may be present in some patients with vasculitis.
Primary and Secondary Vasculitis
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Primary Vasculitis:
- Large vessel: Giant cell (temporal) arteritis / Takayasu's arteritis
- Medium vessel: Polyarteritis Nodosa
- Small/Medium vessel: Wegener's granulomatosis / Churg-Strauss syndrome / Microscopic polyangiitis
- Small vessel: Henoch-Schönlein Purpura / Essential mixed cryoglobulinemia
- Behçet's' disease
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Secondary Vasculitis:
- Drug-induced (e.g., amphetamines)
- Infection-related (e.g., meningococcal septicemia)
- Malignancies
- Connective tissue diseases
Henoch-Schönlein Purpura (HSP)
- An IgA vasculitis that causes a purpuric rash affecting the lower limbs and buttocks in children.
- Inflammation in affected organs arises from IgA deposits in small blood vessels of the skin, joints, gastrointestinal tract, and kidneys.
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Description
This quiz explores the differentiation of lymphoid progenitors into T-cells and B-cells and their roles in the immune system. It covers key concepts such as phagocytosis by neutrophils and macrophages and the function of the complement system. Test your understanding of how these components contribute to both specific and innate immunity.
