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Foundations of Disease > Exam 2: Immunodeficiencies > Flashcards

Exam 2: Immunodeficiencies Flashcards

1
Q

Primary Immunodeficiencies

A

Results from intrinsic defects in cells and/or organs of the immune system.

Generally due to genetic defects

Children to Adult ratio 3:2

Male to female ratio 5:1

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2
Q

Secondary Immunodeficiencies

A

Results from extrinsic factors such as malnourishment, disease, malignancy, medical treatment, or environmental exposure.

The more common type of immunodeficiency.

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3
Q

Recurrent Infections

with

Encapsulated Extracellular Bacteria

A
  • Suggestive of deficiency in:
    • Ab / B-cells
    • Complement
    • Phagocytic cells
  • Examples:
    • Superficial skin infections
    • Ear infections
    • Septicemia
  • Some are also susceptible to certain viruses and intestinal parasites
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4
Q

Recurrent Infections

with

Intracellular Pathogens

A

Suggestive of T-cell deficiencies.

Typically suffer from infections with microorganisms that normal individuals rapidly develop resistance against.

Examples:

Viruses, Mycobacteria, Fungal, Protozoa, Candida, Pneumocystis

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5
Q

B-cell Immunity

Testing

A
  1. Quantification
    • B-cells
      • Flow cytometry
        • CD19+
        • CD20+
        • CD21+
    • Ig levels (total, classes, and subclasses)
      • ELISA
      • RIA
      • Radial immunodiffusion
  2. Function
    • Immunize patient with protein or carbodydrate antigen
    • Measure Ab levels 2-4 weeks later
    • Compare titers of different Ig classes
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6
Q

T-cell Immunity

Testing

A
  1. Quantification
    • Flow cytometry
      • CD3+ ⇒ all mature T-cells in peripheral blood
      • CD4+ ⇒ helper T-cells
      • CD8+ ⇒ cytotoxic T-cells
      • CD25+ (α-subunit of IL-2R) ⇒ activated T-cells
  2. Function
    • In vivo
      • DTH testing using panel of Ag which patient has been immunized to in the past
      • Positive type IV hypersensitivity reaction at site of injection 48-72 hours later suggestive of proper function
    • In vitro
      • Mitogen or specific antigen-induced proliferation
      • Mixed lymphocyte reaction
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7
Q

μ-defect

Agammaglobulinemia

A
  • Defect in μ heavy chain gene
  • Inability to mature from pro-B cell to pre-B cell
  • See complete absence B-cells and Ab
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8
Q

X-linked Aggamaglobulinemia

(XLA)

A
  • Defect in Bruton’s tyrosine kinase (Btk)
    • X-linked
  • Inability to differentiate from pre-B cell into immature B cell
  • See complete absence of B-cells and Ab
  • ​​High frequency of:
    • Upper and lower respiratory tract infections
    • Bacterial meningitis
    • Septicemia
  • Treat with IV-Ig & abx prophylaxis
    • Males usually die by 4th decade due to obstructive lung disease secondary to recurrent URIs
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9
Q

Hyper IgM Syndrome

(HIGM)

A
  • Mutation or deletion of the CD40-ligand gene
    • Defect in T-cells
    • Most forms X-linked, some rare AR types
  • Inability to induce isotype switching
    • Effect exhibited in B-cells
  • See elevated (10x) levels of IgM in adults
    • [IgM] can appear normal in children
  • Treat with pure IV-IgG without IgA to prevent type III hypersensitivities & prophylatic abx
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10
Q

Transient Hypogammaglobulinemia of Infancy

A
  • Onset of normal IgG synthesis delayed as much as 36 months
  • Infant initally protected by materal IgG
  • Delay of endogenous Ig synthesis makes them every susceptible to infections
  • Treat with supplemental IV-IG until issue resolves
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11
Q

Selective IgA Deficiency

A
  • See dramatically decreased levels of IgA
    • Normal levels of IgM and IgG
    • Normal B-cell and plasma cell numbers
  • Unknown etiology
  • Represents a hole in Ig repertoire
  • Most common primary immunodeficiency in the USA
  • See increased sinopulmonary infections
  • DO NOT have significantly increased susceptibility to recurrent infections
  • Make anti-IgA antibodies → can see anaphylaxis following plasma transfusion
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12
Q

IgG Subclass Deficiencies

A
  • Abnormalities in one or more subclasses of IgG
  • Normal B cell and plasma cell numbers
  • Varied immune defects based on effected class
  • Can go undetected
  • May see absent IgG levels in infant d/t failure of placental transfer
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13
Q

Common Variable Immunodeficiency

(CVID)

A
  • Heterlogous group of disorders with reduced serum Ig levels
  • Peripheral T-cell and B-cell levels normal
  • Develops during second or later decade
  • Cause unknown
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14
Q

DiGeorge Syndrome

(Congenital Thymic Aplasia)

A
  • Small, absent, or “misplaced” thymus
  • Low or absent T-cell population and function
  • Increased susceptibility to intracellular pathogens which generally improves with age
    • Likely due to extrathymic T-cell maturation
  • B-cell function variable
    • Serum IgG levels often normal
  • Also see:
    • Congenital heart disease
    • Hypoparathyroidism
    • Abnormal facial structures
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15
Q

Chronic Mucocutaneous Candidiasis

A
  • Severe, chronic superficial infections with Candida albicans
  • Likely due to a selective defect in T-cell function
  • Other T & B cell mediated defenses appear normal
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16
Q

Severe Combined Immunodeficiency Disorders

(SCID)

A
  • Heterologous group of disorders w/ multiple etiologies
  • Abnormalities in both T and B cell components
  • Bone marrow transplantation crutial but cause severe GvH reactions
  • Immunological features (all types)
    • All functional T and B cell tests abnormal
    • Minimal if any lymphocytes
    • Abnormal lymphoid structure
17
Q

X-Linked SCID

A
  • Defect in γ-subunit of the IL-2 receptor
    • Subunit common to IL-2, IL-4, IL-7, IL-9, and IL-15 cytokine receptors
    • Responsible for intracellular signal tranduction
  • See normal B cell numbers
  • ~50% of all SCID patients
18
Q

Functional Ablation of Multiple Cytokines

(SCID)

A
  • Causes
    • Abnormality in a transcription factor
      • Causes defect in transcription of several cytokine genes
    • Cytokine receptor-related signaling defect
      • Ex. JAK-3 used in IL-2R signaling
19
Q

Adenosine Deaminase Deficiency

(ADA)

A
  • Defect in ADA enzyme
    • Needed for normal purine metabolism
    • Products toxic to lymphocytes accumulate
  • See abnormal T and B cell numbers and function
  • Associated with 25% of SCID patients

*See similar manifestation with purine nucelotide phosphorylase (PNP) deficiency

20
Q

Bare Lymphocyte Syndrome

A
  • Defective MHC expression
  • Classified into three types:
    • Type I = no MHC I
    • Type II = no MHC II
    • Type III = no MHC I or II
  • Only those without class II MHC consistently show immunodeficiency
    • Failure of peptide presentation
    • Lack of T and B cell collaboration
    • ↓ CD4+ T-cell counts
    • Abnormal B-cell function
21
Q

Congenital Agranulocytosis

A
  • Virtual lack of neutrophils
  • Myeloid stem cells fail to differentiate past promyelocyte stage
  • ? abnormality in G-CSF production
  • See bacterial infections in the first month of life
  • Treat with abx and recombinant G-CSF
22
Q

Secondary Neutrophil Immunodeficiencies

A

Caused by:

  • Radiation or chemotherapy induced neutropenia
  • Autoimmune disease (e.g. SLE)
  • Transiently in children following viral infections
    • Main reason why viral infections typically followed by bacterial infections
23
Q

Leukocyte Adhesion Deficiencies

(LAD)

A

LAD-1

  • Defect in integrin component CD18
    • Component of LFA-1
    • Defect on the lymphocyte side
  • CD18 required for:
    • Firm adhesion of ALL LEUKOCYTES
    • C3b opsonization monocyte recruitment
    • CTL and NK cell adherence to targets
    • TH and B-cell interactions

LAD-2

  • Blockage of sialyl-Lewisx production
    • Defect on the endothelial side
  • Results in loss of rolling
24
Q

Hyper IgE Syndrome

A

“Job Syndrome”

  • Usually due to muation in STAT3
  • Results in:
    • High IgE levels
    • Phagocytes fail to consistantly respond normally to chemotactic stimuli
    • Blocks maturation of TH17 cells
  • Characterized by:
    • Chronic eczematous dermatitis
    • Recurrent skin, lung, and bone abscesses
    • Ear and sinus infections
    • Abnormal facial features
    • Hyperextensibility
    • Scoliosis
    • Osteopenia
25
Q

Chédiak-Higashi Syndrome

A
  • Abnormal microtubule function
  • Causes abnormal chemotaxis and lysosomal fusion in phagocytic cells
  • Characterized by:
    • Severe immunodeficiency with neutropenia
    • NK cell abnormalities
  • See giant cytoplasmic granular inclusions in leukocytes and platelets
26
Q

Chronic Granulomatous Disease

(CGD)

A
  • Defect in NADPH oxidase
    • X-linked and AR forms
  • Neutrophils & macrophages incapable of oxygen-mediated killing
  • Because Ag not cleared, a cell-mediated response develops and granuloma formed
  • Characterized by disseminated granulomatous lesions
  • Treat with bone marrow transplantation
  • Test for it using NBT dye reduction assay
27
Q

Myeloperoxidase (MPO) Deficiency

A
  • Most common neutrophil defect
  • Autosomal recessive
  • Isolated MPO deficiency is NOT associated with clinically compromised defenses
  • Microbicidal activity of neutrophils delayed but not absent
  • Issue with automated cell counters
28
Q

Complement Deficiencies

A
  1. Classical complement components (C1, C4, or C2)
    • Increased risk of developing immune complex diseases
  2. C3
    • Increased rate of bacterial infections
    • Decreased opsonization
  3. Terminal complement components (C5, C6, C7, C8) or alternative pathway components
    • Increased susceptibility to disseminated Neisseria gonorrhoeae and Neisseria meningitides infections
29
Q

Hereditary Angioedema

A
  • Due to deficiency of C1 esterase inhibitor
  • Uncontrolled formation of vasoactive substances
  • See ↑ capillary permeability and edema
  • Fatality from laryngeal edema
30
Q

Secondary Immunodeficiency

Types

A
  1. Protein-caloric malnutrition
    • Most common cause of immunodeficiency
  2. Metabolic disorders
    • Diabetes
    • Cushing’s syndrome
  3. Surgery and trauma
    • Splenectomy
    • Extensive trauma
    • Burns
  4. Aging
    • Produce less specific Ab
    • Decline of T cell proliferation & IL-2 production
    • Decreased DTH responses
    • Changes in innate immunity
    • Likely due to immune dysregulation
  5. Malignancies and hematological disease
    • Lymphoma
    • Leukemia
  6. Immunosuppressive agents
  7. Infectious processes
    • HIV
    • Cytomegalovirus infections

Foundations of Disease (46 decks)

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