03/15c Inborn and Acquired Immunodeficiencies

Question 1

What is immunodeficiency?

Answer 1

Increased susceptibility to infection, certain types of cancer, and sometimes increased incidence of autoimmunity

Question 2

What are the two broad categories of immunodeficiency disorders?

Answer 2

Congenital

Acquired

Question 3

What types of immune defects result from congenital immunodeficiencies?

Answer 3

Defects in innate immunity
Defects in B cell and T cell development, activation, and function
Severe combined immunodeficiencies

Question 4

What two functions are typically affected by defects in innate immunity?

Answer 4

Complement pathway

Phagocyte function

Question 5

What are the typical clinical presentations of defects in the complement pathway?

Answer 5

Failure to clear circulating immune complexes and higher incidence of SLE
Susceptibility to infection with pyogenic encapsulated bacteria
Propensity for disseminated infections by Neisseria species

Question 6

What are the typical clinical presentations of defects in phagocytes? List a few specific diseases as well

Answer 6

Infections of the skin and respiratory tract with bacteria or fungi (particularly Aspergillus and Candida)
Chronic granulomatous disease
Leukocyte adhesion deficiency
Chédiak-Higashi syndrome
TLR signaling defects (rare)

Question 7

What is chronic granulomatous disease? Describe its mechanisms, symptoms, and treatment

Answer 7

Defective production of ROS and failure to kill microbes by phagocytes, due to a defect in phagocyte oxidase
Results in recurrent infections with catalase-positive intracellular bacteria and fungi
Infections stimulate chronic cell-mediated immune responses and formation of granulomas
Treatment - aggressive antibiotic therapy, IFN-gamma

Question 8

What are leukocyte adhesion deficiencies? Describe their mechanisms and symptoms

Answer 8

Autosomal recessive disorders caused by defects in leukocyte and endothelial adhesion molecules
Results in a failure of neutrophil recruitment to site of infections and inability to make pus
Symptoms - early severe periodontitis and recurrent infections

Question 9

What is Chédiak-Higashi syndrome?

Answer 9

Defect in phagosome-lysosome fusion in phagocytic cells as a result of mutations in a lysosomal trafficking regulator protein
Results in giant lysosomes in phagocytic cells and general lysosomal defects in melanocytes, platelets, and the CNS
Symptoms - recurrent infections by pyogenic bacteria

Question 10

By what features are B cell defects diagnosed?

Answer 10

Reduced levels of serum Ig
Defective antibody responses to vaccination
Reduced numbers of B cells
Absent plasma cells in tissues

Question 11

What are agammaglobulinemias?

Answer 11

Defects in B cell development that result in reduced number of B cells and all serum Igs
Most common form is X-linked autosomal recessive, and is due to a defect in Bruton’s tyrosine kinase

Question 12

What are hypogammaglobulinemias?

Answer 12

Defects in B cell differentiation that lead to deficiencies in one or a few Ig isotypes
Number of B cells is usually normal

Question 13

What is the most common primary immunodeficiency? Describe its mechanisms and symptoms

Answer 13

IgA deficiency due to a block in differentiation of B cells
Results in low levels of serum IgA
Symptoms - recurrent intestinal and respiratory infections (often asymptomatic), possible anaphylaxis with transfusions

Question 14

What is common variable immunodeficiency?

Answer 14

Block in differentiation of B cells into plasma cells that results in reduced levels of serum Ig, impaired antibody responses, and normal B cell numbers
Symptoms - high frequency of autoimmune disorders and tumors
Presentation and pathogenesis are highly variable

Question 15

What are hyper-IgM syndromes?

Answer 15

Defects in somatic mutations and class-switching, often due to a lack of T cell help, that result in elevated IgM and decreased IgG and IgA
Normal B cell numbers
Caused by mutations in CD40L (X-linked), AID, and CD40

Question 16

What are the symptoms of X-linked hyper-IgM syndrome?

Answer 16

Increased infection due to lack of IgG, IgA, and IgE
Defects in cell-mediated immunity
Most common hyper-IgM syndrome

Question 17

By what features are T cell defects diagnosed?

Answer 17

Reduced numbers of peripheral blood T cells
Poor responses to T cell activators
Deficient cutaneous DTH reactions to ubiquitous microbial antigens, like Candida

Question 18

Why are isolated T cell deficiencies typically limited to CD8 defects?

Answer 18

Because a defect in CD4 cells (helper T cells) automatically leads to a defect in B cells

Question 19

What is Bare Lymphocyte Syndrome Type I?

Answer 19

Deficiency in MHC I due to mutations in TAP
Results in decreased CD8 cell numbers and function, activated NK cells, perforin deficiencies, and granule fusion defects

Question 20

What causes severe combined immunodeficiencies? List the general and a few specific causes

Answer 20

Deficiencies in B and T cells, OR in just T cells which results in defects in humoral immunity
MANY causes, including defects in ADA, the common gamma chain, and V(D)J recombination

Question 21

What is the result of adenosine deaminase deficiency?

Answer 21

SCID (most common cause)
Causes accumulation of deoxyadenosine and its precursors (toxic to rapidly proliferating cells)
Results in defects in lymphocyte development and thus reduced B and T cells

Question 22

What is the common gamma chain?

Answer 22

A common motif of MANY cytokine receptors, including IL-2, 4, 21, 7, 9, and 15
Gene is found on the X chromosome

Question 23

What is the result of common gamma chain deficiency?

Answer 23

X-linked SCID (most common cause)
Result in a lack of growth of immature T cells, deficient NK cells, and no T cell help
B cell numbers are usually normal

Question 24

What are the common characteristics and clinical presentations of SCID?

Answer 24

Deficiencies in both humoral and cell-mediated immunity, resulting in a high susceptibility to all sorts of infections
Presentations - failure to thrive, chronic diarrhea, recurrent infections
Usually fatal in the first few years of life

Question 25

What is Wiskott-Aldrich syndrome?

Answer 25

Mutation in WASP (WA syndrome protein) - expressed in leukocytes and megakaryocytes
Symptoms - eczema, thrombocytopenia with small platelets, bleeding, infections, low IgM levels

Question 26

What is ataxia telangiectasia?

Answer 26

Autosomal recessive deficiency in a DNA repair protein that results in accumulated DNA damage, defects in VDJ recombination and class switching, and decreased B and T cells
Symptoms - progressive ataxia, telangiectasias, variable immunodeficiency 
Often present with recurrent sinopulmonary infections

Question 27

What are the two main causes of acquired immunodeficiencies?

Answer 27

1) Biologic complication of another disease process

2) Complication of therapy for other diseases - the most frequent cause

Question 28

What are the mechanisms by which HIV causes immunodeficiency?

Answer 28

Direct cytopathic effects of infection of CD4 cells - decreased T cell functions
Also infects and injures macrophages and dendritic cells