Immunodeficiency Disorders

Question 1

Recurrent vs. Chronic Immunodeficiency Causes

Answer 1

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

Question 2

Ig Heavy Chain Deletions

Answer 2

Ig Heavy Chain Deletions: IgG1, 2, and 4 absent from chromosomal deletions

Question 3

Defects in T cell Receptor Complex

Answer 3

Defects in T cell Receptor Complex: decreased T cells/cell mediated immunity from mutations in genes encoding CD3 proteins

Question 4

Defects in Th1 Responses

Answer 4

Defects in Th1 Responses: decreased T cell mediated macrophage activation from mutations in IL-12 receptors or IFN gamma

Question 5

Defects in Th17 Responses

Answer 5

Defects in Th17 Responses: decreased T cell mediated inflammatory responses from mutations in STAT3, IL-17

Question 6

X linked Lymphoproliferative Syndrome

Answer 6

X linked Lymphoproliferative Syndrome: uncontrolled EBV induced B cell proliferation from mutations in SAP

Question 7

Transient Hypogammaglobulinemia of Infancy

Answer 7

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

Question 8

X-linked Hyper IgM syndrome

Answer 8

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

Question 9

Selective IgA Deficiency

Answer 9

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

Question 10

Bruton’s X-linked Agammmaglobulinemia

Answer 10

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

Question 11

CVID (common variable immunodeficiency)

Answer 11

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

Question 12

Complications of B cell Deficiency

Answer 12

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

Question 13

SCID

Answer 13

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

Question 14

Defects in SCID Disorders

Answer 14

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

Question 15

Defects in Thymus Functions

Answer 15

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

Question 16

Chronic Granulomatous Disease

Answer 16

Chronic Granulomatous Disease: defective production of reactive O2 intermediates by phagocytes via mutations in genes encoding components of oxidase enzyme

Question 17

Leukocyte Adhesion Deficiency 1

Answer 17

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

Question 18

Leukocyte Adhesion Deficiency 2

Answer 18

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

Question 19

Complement C3, C2/4 Deficiencies

Answer 19

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

Question 20

Chediak Higashi Syndrome

Answer 20

Chediak Higashi Syndrome: defective lysosomal function in neutrophils, DC, macrophages, and NK cells via mutation of lysosomal regulatory proteins

Question 21

HSV 1 Encephalitis

Answer 21

HSV 1 Encephalitis: defective antiviral immunity in the CNS via mutations in gene encoding TLR3

Question 22

Recurrent Bacterial Pneumonia

Answer 22

Recurrent Bacterial Pneumonia: defective innate immune responses to pyogenic bacteria via mutations in gene encoding MyD88

Question 23

Hereditary Angiodema and C5-C9 Deficiency

Answer 23

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

Question 24

Common Causes of Secondary Immunodeficiency

Answer 24

Cancer (immunoproliferative diseases)
Cytotoxic drugs or radiation
Malnutrition
Splenectomy
Immunosuppressive therapies
Stress/emotions (neuroendocrine effects)
Aging (thymic atrophy, other)
Infection (such as HIV/AIDS)

Question 25

Systemic Non-Lymphoid Malignancy and Lymphoproliferative Disease

Answer 25

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

Question 26

Malnutrition ad Vitamin/Mineral Defiency

Answer 26

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

Question 27

Mechanism of Loss of Immune Function in Splenectomized Patients

Answer 27

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.

Question 28

Mechanism of Loss of Immune Function in Patients with Immune Mediated Disorders

Answer 28

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

Question 29

Mechanism of Loss of Immune Function in Patients with Psychological Stress

Answer 29

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

Question 30

Mechanism of Loss of Immune Function in Aging (Immunosenescence)

Answer 30

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)

Question 31

Mechanism of Loss of Function Due to Infections

Answer 31

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)

Question 32

Protein Loss, Burns, and Chronic Diseases

Answer 32

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

Question 33

Measures of Immune Status

Answer 33

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

Question 34

Bacterial vs. Viral/Fungal Infections

Answer 34

Bacterial infection indicates antibody, complement or phagocyte defects

Viral or fungal infections indicate T cell defects

Question 35

Immunomodulatory Agents

Answer 35

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

Question 36

Broad Non-Specific Immunosuppression

Answer 36

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