Immunodeficiency Disorders Flashcards
Recurrent vs. Chronic Immunodeficiency Causes
Antibody deficiency, Phagocyte deficiencies, or Complement protein deficiencies are associated with RECURRENT INFECTIONS with extracellular pyogenic bacteria (pneumonia, otitis media, skin infections)
Deficiency in Cell-mediated immunity is associated with RECURRENT OR CHRONIC viral, fungal, or protozoal diseases
Ig Heavy Chain Deletions
Ig Heavy Chain Deletions: IgG1, 2, and 4 absent from chromosomal deletions
Defects in T cell Receptor Complex
Defects in T cell Receptor Complex: decreased T cells/cell mediated immunity from mutations in genes encoding CD3 proteins
Defects in Th1 Responses
Defects in Th1 Responses: decreased T cell mediated macrophage activation from mutations in IL-12 receptors or IFN gamma
Defects in Th17 Responses
Defects in Th17 Responses: decreased T cell mediated inflammatory responses from mutations in STAT3, IL-17
X linked Lymphoproliferative Syndrome
X linked Lymphoproliferative Syndrome: uncontrolled EBV induced B cell proliferation from mutations in SAP
Transient Hypogammaglobulinemia of Infancy
B cell deficiency
Loss of maternal IgG and delayed onset of IgG synthesis by infant
Symptoms at 9 mo. to 2 yr of age
Treat with intravenous immunoglobulin (IVIG) every couple months because of half life of Ig’s
Pre-birth: IgG dominates from mother through the placenta and low levels of IgM are produced by fetus
At birth: immune system develops and develops own IgG, IgM predominates, and IgA is very slow and does not reach high levels until puberty
If delayed IgG production (their own) which will cause recurrent infections but resides over time
X-linked Hyper IgM syndrome
Defective CD-40L expression by T cells
B cells present, IgM but no IgG or IgA
Poorly organized germinal, centers, no B memory
absent DC-T cell interaction va CD40-CD40L reduces T cell activation thus promoting malignancies
Treat with IVIG or bone marrow transplantation
Selective IgA Deficiency
Occurs in 1:600-1:800 people presenting at any age
Undetectable or low IgA, normal IgG and IgM
Possible but not uniform connection with increased sinopulmonary and gastrointestinal infections and allergies
20% make adverse anti-IgA responses to transfusions or replacement therapy
Bruton’s X-linked Agammmaglobulinemia
Defective btk gene (Bruton’s tyrosine kinase)
B cell maturation arrested at pre-B-stage
Circulating mature B cells absent
T cells present
Infants have recurrent infections with pyogenic bacteria between ages 4 months and 2 years
Treat with replacement Ig
CVID (common variable immunodeficiency)
Most common primary Ab deficiency (heterogeneous group of disorders)
1/3 of patients have defects in CMI as well
Recurrent infection, autoimmunity, lymphomas
90% diagnosed in adulthood
Poor Ab response to infection with low IgG &IgA, normal or low IgM and B cell numbers
Defects in cytokine receptors & costimulators
Replacement Ig therapy
Complications of B cell Deficiency
Respiratory tract or GI tract sepsis
Common organisms (pyogenic bacteria): staphylococci, streptococci, Haemophilus
Less common organisms: enteroviruses (echovirus, poliovirus) or other bacteria (salmonella, campylobacter)
Rare incidence of malignancy
SCID
Primary defects in T cell differentiation or function result in combined loss of T and B cell function
Usually present in first few months of life
Other systems often affected
Severe Combined Immunodeficiency Disease (SCID) results from complete loss of B and T cell function
Present early with persistent infection and failure to thrive
Therapeutic and prophylactic antibiotics are appropriate.
Administration of live vaccines or transfusions must be avoided
Bone marrow transplantation is the treatment of choice
Gene therapy is promising
Defects in SCID Disorders
X-linked SCID: defect in IL-7 receptor (g chain)
Autosomally inherited SCIDs: adenosine deaminase deficiency or purine nucleotide phosphorylase deficiency
DNA recombinase deficiencies (RAG1 or RAG 2 deficiency) cause arrested lymphocyte development due to failure to rearrange antigen receptor genes
Defects in Thymus Functions
Bare Lymphocyte syndrome: absence of MHC II gene products in thymus stops positive selection of CD4 T cells in the thymus
MHC Class I deficiency in thymus causes lack of CD8 T cells
Congenital thymic aplasia (DiGeorge syndrome) eliminates T cell maturation
*All block T cell development
Chronic Granulomatous Disease
Chronic Granulomatous Disease: defective production of reactive O2 intermediates by phagocytes via mutations in genes encoding components of oxidase enzyme
Leukocyte Adhesion Deficiency 1
Leukocyte Adhesion Deficiency 1: absent or deficient expression of beta2 integrins so leukocytes cannot adhere to wall via mutation in beta chain of beta2 integrins
Leukocyte Adhesion Deficiency 2
Leukocyte Adhesion Deficiency 2: absent of deficient expression of leukocyte ligands for endothelial E and P selectins causing failure of migration via mutations of protein for synthesis of selectins
Complement C3, C2/4 Deficiencies
Complement C3 Deficiency: defect in complement cascade activation via mutation in the C3 gene
Complement C2, C4 Deficiency: deficient activation of classical pathway via mutations of C2 and C4; can cause lupus like disease development
Chediak Higashi Syndrome
Chediak Higashi Syndrome: defective lysosomal function in neutrophils, DC, macrophages, and NK cells via mutation of lysosomal regulatory proteins
HSV 1 Encephalitis
HSV 1 Encephalitis: defective antiviral immunity in the CNS via mutations in gene encoding TLR3
Recurrent Bacterial Pneumonia
Recurrent Bacterial Pneumonia: defective innate immune responses to pyogenic bacteria via mutations in gene encoding MyD88
Hereditary Angiodema and C5-C9 Deficiency
Hereditary Angioedema
C1 Inhibitor deficiency (most common inherited complement deficiency)
C5,C6,C7,C8, or C9 Deficiency
Recurrent bacterial meningitis due defective membrane attack complex
Common Causes of Secondary Immunodeficiency
Cancer (immunoproliferative diseases) Cytotoxic drugs or radiation Malnutrition Splenectomy Immunosuppressive therapies Stress/emotions (neuroendocrine effects) Aging (thymic atrophy, other) Infection (such as HIV/AIDS)
Systemic Non-Lymphoid Malignancy and Lymphoproliferative Disease
Systemic non-lymphoid malignancy
Unknown underlying immune defect
Depression of bone marrow stem cells and peripheral lymphocyte proliferation by anti-proliferative or cytotoxic cancer chemotherapy or radiation
Lymphoproliferative disease
Disruption/crowding/replacement of normal cells in marrow and lymphoid organs
loss of antibody responses in CLL
Loss of normal polyclonal Ab response in multiple myeloma
neutropenia
Effects of suppressive chemotherapy as above
Malnutrition ad Vitamin/Mineral Defiency
Malnutrition (severe protein/calorie deficiency)
General depression of protein synthesis reduces CMI, phagocyte function, complement and antibody synthesis
Leptin deficiency affects T cell responses?
Vitamin or mineral deficiency
Zinc deficiency impairs T cell and DC function and reduces killing functions of phagocytes
Mechanism of Loss of Immune Function in Splenectomized Patients
Increases susceptibility to bacteremias with encapsulated bacteria such as Streptococus pneumoniae
Specialized macrophages and B cells in spleen are critical for clearance of bacteria from blood and for T-independent antibody responses to polysaccharide antigens.
Mechanism of Loss of Immune Function in Patients with Immune Mediated Disorders
Immune suppression by Anti-inflammatory or Immunosuppressive drugs used to treat allergies, autoimmune & auto-inflammatory disorders, and to suppress transplant rejection
Corticosteroids (prednisone): broad spectrum inhibition of cytokine gene expression, phagocyte migration, lymphocyte function
Anti-rejection drugs: suppress lymphocyte proliferation
Mechanism of Loss of Immune Function in Patients with Psychological Stress
Stress/emotions
Neuroendocrine modulation of immune components
Cortisol levels increase in response to stress via the Hypothalamic-Pituitary-Adrenal axis (HPA)
Stressed, then have HPA reaction to cause increase in cortisol, which increases risk of infection
Mechanism of Loss of Immune Function in Aging (Immunosenescence)
Clinical significance of immunosenescence
Increased rate of cancer (CLL)
Higher rate of infectious disease mortality
Decreased efficacy of vaccines
Increased rates of TB reactivation and shingles
Mechanisms of immunosenescence Bone marrow compartment decline (fewer lymphocyte progenitor cells) Thymic involution (Decline in generation of naïve T cells) “Replicative senescence” of predominant T memory population expanded by chronic stimulation (many are CMV-specific)
Mechanism of Loss of Function Due to Infections
Microbe activation of Treg cells may cause local immune suppression that promotes chronic infection
Hepatitis C virus, Herpes simplex, Leishmania major
Diversion of lymphocytes to a local infection site may suppress systemic responses (such as DTH skin reaction)
Microbial toxins cause cellular apoptosis Staphylococcal superantigens (nonspecific T cell proliferation and apoptosis causes general immunosuppression) Anthrax toxin disrupts macrophage and DC function
Direct infection of immune cells with direct or indirect injury or loss of cell function Measles virus (Dendritric cells) EBV (B cells), HIV (T cells)
Protein Loss, Burns, and Chronic Diseases
Protein loss sufficient to cause low antibody levels and hypoproteinemia
Kidney disease (nephrotic syndrome)
Protein-losing enteropathy (Crohn’s disease)
Burns
Burns Loss of skin barrier & innate immune functions Protein loss (parallel drop in Ab level) Systemic suppression (due to regulatory anti-inflammatory response?)
Chronic Diseases (ex. Diabetes): reduced phagocyte killing
Measures of Immune Status
Inherited or acquired immune deficiency is indicated by
Clinical Evidence:
increased numbers of infections or persistence of infections
Lab Evidence:
Altered levels or absence of immune cells or molecules
Diminished or absent function of cells or molecules as shown by direct lab assessment of function
Bacterial vs. Viral/Fungal Infections
Bacterial infection indicates antibody, complement or phagocyte defects
Viral or fungal infections indicate T cell defects
Immunomodulatory Agents
Immunosuppressive agents:
Anti-inflammatory corticosteroids
Cytotoxic agents (azathioprine, cyclophosphamide)
T cell signaling inhibitors (cyclosporin A, tacrolimus, rapamycin)
Biological agents:
Monoclonal antibodies
Recombinant cytokines
Adoptive cell transfer (NK cells, bone marrow transplant)
Immunizations: Active vaccines Adjuvants Passive immunization and Intravenous immune globulin (IVIG) Tumor vaccines and immunotoxins
Broad Non-Specific Immunosuppression
Broad nonspecific immunosuppression inhibits both harmful and protective immune responses
Side effects = opportunistic infection
Antigen-specific immunosuppressive therapies are ideal because general immune responses are not compromised
