Immunodeficiencies Flashcards
Primary Immunodeficiencies
Result 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
Secondary Immunodeficiencies
Result from extrinsic factors such as malnourishment, disease, malignancy, medical treatment, or environmental exposure.
The more common type of immunodeficiency.
Recurrent Infections
with
Encapsulated Extracellular Bacteria
Suggestive of deficiency in:
Immunoglobulin / B-cells
Complement
Phagocytic cells
Examples:
superficial skin infections
ear infections
septicemia
Some are also susceptible to some viruses and certain intestinal parasites.
Recurrent Infections
with
Intracellular Pathogens
Suggestive of T-cell deficiencies.
Typically suffer from infctions with microorganisms that normal individuals rapidly develop resistance against.
Examples:
Viruses
Mycobacteria
Fungal
Protozoan pathogen
Candida
Pneumocystis
B-cell Immunity
Testing
-
Quantification
- B-cells
- Flow cytometry
- CD19+
- CD20+
- CD21+
- Flow cytometry
- Ig levels (total, classes, and subclasses)
- ELISA
- RIA
- radial immunodiffusion
- B-cells
-
Function
- Immunize patient with protein or carbodydrate antigen
- Quantitate Ab levels 2-4 weeks later
- Compare titers of different Ig classes
T-cell Immunity
Testing
-
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
- Flow cytometry
-
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
- In vivo
X-linked Aggamaglobulinemia
(XLA)
- 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 & antibody prophylaxis
- Males usually die by 4th decade due to obstructive lung disease secondary to recurrent URIs
Agammaglobulinemia
Secondary to mutated μ heavy chain gene
- Defect in μ heavy chain gene
- Inability to mature from pro-B cell to pre-B cell
- See complete absence B-cells and Ab
Hyper IgM Syndrome
(HIGM)
- 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
Transient Hypogammaglobulinemia of Infancy
- Onset of normal IgG synthesis delayed as much as 36 months
- Infant initally protected by materal IgG
- Daly of endogenous Ig synthesis makes them every susceptible to infections
- Treat with supplemental IV-IG until issue resolves
Selective IgA Deficiency
- See dramatically decreased levels of IgA
- Normal levels of IgM and IgG
- Normal B cell and plasma cell numbers
- Unknown etiology
- 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
IgG Subclass Deficiencies
- 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
Common Variable Immunodeficiency
(CVID)
- 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
DiGeorge Syndrome
(Congenital Thymic Aplasia)
- 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
Chronic Mucocutaneous Candidiasis
- 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
Severe Combined Immunodeficiency Disorders
(SCID)
Heterologous group of disorders.
Abnormalities in both T and B cell components.
Multiple etiologies.
Bone marrow transplantation crutial but can see severe GvH reactions.
- Immunological features (all types)
- All functional T and B cell tests abnormal
- Minimal if any lymphocytes
- Abnormal lymphoid structure
X-Linked SCID
- 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
- See normal B cell numbers
- ~50% of all SCID patients
Functional Ablation of Multiple Cytokines
SCID
- Can occur due to abnormality in a transcription factor
- Causes defect in transcription of several cytokine genes
- Or a cytokine receptor-related signaling defect
- Ex. JAK-3 used in IL-2R signaling
Adenosine Deaminase Deficiency
(ADA)
- 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.
Bare Lymphocyte Syndrome
- Defective MHC expression
- Classified into three types:
- Type I = no MHC I
- Type II = no MHC II
- Type II = no MHC I or II
- Only those without class II MHC consistently show immunodeficiency
- Failure of peptide presenation
- Lack of T and B cell collaboration
- Decreased CD4+ T-cell and abnormal B-cell function
Congenital Agranulocytosis
- 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
Secondary Neutrophil Immunodeficiencies
- 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
Leukocyte Adhesion Deficiencies
(LAD)
LAD-1
- Defect in integrin component CD18
- Component of LFA-1
- CD18 required for:
- endothelial adhesion of ALL LEUKOCYTES
- C3b opsonization monocyte recruitment
- CTL and NK cell adhereance to targets
- TH and B cell interactions
LAD-2
- Blockage of sialyl-Lewisx production
- Loss of rolling
Hyper IgE Syndrome
(Job’s Syndrome)
- Usually due to muation in STAT3
- High IgE levels
- Phagocyte numbers and function normal but fail to consistantly respond normally to chemotactic stimuli
- Characterized by:
- chronic eczematous dermatitis
- recurrent skin, lung, and bone abscesses
- ear and sinus infections
Chédiak-Higashi Syndrome
- 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
Chronic Granulomatous Disease
(CGD)
- Defect in NADPH oxidase
- Neutrophils & macrophages incapable of oxygen-mediated killing
- Because Ag not cleared, a cell-mediated response develops and granuloma formed
- Characterized by disseminated granulomatous lesions
- X-linked and AR forms
- Treat with bone marrow transplantation
- Test for it using NBT dye reduction assay
Myeloperoxidase (MPO) Deficiency
- 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
Complement Deficiencies
-
Classical complement components (C1, C4, or C2)
- Increased risk of developing immune complex diseases
-
C3
- Increased rate of bacterial infections
- Decreased opsonization
-
Terminal complement components (C5, C6, C7, C8) or alternative pathway components
- Increased susceptibility to disseminated Neisseria gonorrhoeae and Neisseria meningitides infections
Hereditary Angioedema
- Due to deficiency of C1 esterase inhibitor
- Uncontrolled formation of vasoactive substances
- See capillary permeability and edema
- Fatality from laryngeal edema
Secondary Immunodeficiency
Types
- Protein-caloric malnutrition
- Most common cause of immunodeficiency
- Metabolic disorders
- Diabetes
- Cushing’s syndrome
- Surgery and trauma
- Splenectomy
- Extensive trauma
- Burns
- 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
- Malignancies and hematological disease
- Lymphoma
- Leukemia
- Immunosuppressive agents
- Infectious processes
- HIV
- Cytomegalovirus infections
