Inherited Acquired Immune Deficiencies

Question 1

What is X-Linked agammaglobulinemia?

Answer 1

X-linked mutation in Bruton’s tyrosine kinase

BTK is required for B cell production in the bone marrow (signal transduction).

Patient has very few B cells and hence no humoral immune system.

Susceptible to extracellular bacterial and many viral pathogens because cannot neutralize virions
e.g. influenza

Classical phenotype: underdeveloped tonsils

Question 2

A patient who has recurrent infections and underdeveloped tonsils probably has what deficiency?

Answer 2

X-linked agammaglobulinemia

Question 3

A deficiency in Bruton’s tyrosine kinase results in what disease?

Answer 3

X-linked agammaglobulinemia

Question 4

What is Pre B-cell receptor deficiency?

Answer 4

Mutation in lambda 5 gene.

The surrogate light chain is absent during B cell development (surrogate holds BCR intact during light chain recombination).

Developing B cell receptors become unstable and undergo apoptotic death.

PROFOUND B cell deficiency.

Susceptible to extracellular bacteria and many viral pathogens.

Question 5

A deficiency in lambda 5 gene results in what?

Answer 5

Pre B-cell receptor deficiency

Question 6

What are 2 types of X-Linked Hyper IgM syndromes?

Answer 6

1) Deficiency in CD40 Ligand so T cells cannot activate B cells.
- Results in low Ab production (compared to immunocompetent person)
- Results in only IgM antibodies in system.
- No germinal centers.

2) Deficiency of AID (activation-induced cytidine deaminase)
- Cannot class switch after activation of B cell
- Can activate B cells
- Results in higher IgM levels compared to CD40L def.

Question 7

Deficiency in AID results in what?

Answer 7

Inability to class switch, so high IgM levels when B cells are activated

Question 8

Deficiency in CD40 ligand results in what?

Answer 8

Cannot activate B cells, so
VERY low Ab production
Ab production is only IgM Ab’s

No germinal centers.

Question 9

What is Selective IgA Deficiency?

Answer 9

Genetic mutation where patients do not produce IgA

• Typically, undiagnosed
• Noticed when receiving blood transfusion because patient develops antibodies to the IgA in the blood product.
• – This results in an anaphylactic reaction.

VERY COMMON GENETIC IMMUNODEFICIENCY

Question 10

A patient that goes into anaphylactic response following a blood transfusion most likely has what kind of immune genetic deficiency?

(NOTE: Blood transfusion reactions have MANY reasons other than this condition)

Answer 10

Selective IgA Deficiency

Question 11

What is Selective IgG Deficiency?

Answer 11

Unknown genetic mutation that causes deficiency in IgG isotypes
- Most important:
Deficiency of IgG1 – Results in increased susceptibility to bacteria and viruses
(probably most important because 60-70% of IgG in body is IgG1)

IgG2 Def – Seen in children; Susceptible to encapsulated bacteria

IgG3 Def – Seen in adults

IgG4 Def – Ignore

Question 12

What is the most important form of selective IgG deficiency? Why?

Answer 12

IgG1 deficiency

Majority of IgG in body is IgG1 (60-70%)

Question 13

What is Common Variable Immunodeficiency (CVI)?

Answer 13

Collection of 150 related primary immunodeficiencies that have common features that typically include reduced antibodies = hypogammaglobulinemia.

• Unknown etiologies
• Susceptible to recurring bacterial and some viral pathogens

Question 14

What diagnosis is characteristic of unknown genetic hypogammaglobulinemia with recurring bacterial and viral infections?

Answer 14

Common variable immunodeficiency

Question 15

What is ataxia telangiectasia?

Answer 15

• Inherited defect in the ATM gene (encodes a DNA repair enzyme)
• Typically have clinical triad:
  (1) Ataxia (cerebellar defects)
  (2) Spider angiomas
  (3) Either IgA (most commonly) or IgE deficiency

•• elevated alpha-fetoprotein levels are also common

[Can have T cell depletion and/or T cell & B cell depletion in some cases]

Question 16

A patient that presents with ataxia, spider angiomas and IgA deficiency should be tested for what?

Answer 16

ataxia telangiectasia

Can have IgE deficiency

Question 17

What is an IL-12 Signaling Deficiency?

Answer 17

Either 1) Defective IL-12 heterodimer or 2) Defective IL-12 receptor

• -That leads to small production of IFN-gamma
• —Decreased activation of Th1 CD4 T cells
• —Lack of activation of macrophages

Particularly susceptible to disseminated mycobacterial infections.

Question 18

A patient with persistent disseminated mycobacterial infection and small amount of IFN-gamma should be tested for what deficiency?

Answer 18

IL-12 signaling deficiency

Question 19

What is Job’s Syndrome?

Answer 19

Genetic deficiency of STAT-3 in T-cells

• Cannot make INF-gamma
• Immune responses are polarized towards Th2 responses
• HIGH IgE levels in blood.
• Neutrophils do not respond well to chemokines (unknown reason)

Clinical manifestations:

• Eczema
• Recurrent abscesses with Staph aureus (primarily).
• Characteristic facial features that include a
• –broad nose
• –frontal bossing
• –deep set eyes
• –retention of primary teeth

F.A.T.E.D.
F = coarse facies
A = cold staph Abscesses
T = retained primary Teeth
E = increased igE
D = Dermatologic problems (eczema)

Question 20

A patient with recurrent Staph abscesses, frontal bossing, eczema and retention of primary teeth needs to be tested for what disease?

What is the mechanism of disease?

Answer 20

Job’s Syndrome

Genetic deficiency of STAT-3 in T-cells

• Cannot make INF-gamma
• Immune responses are polarized towards Th2 responses
• HIGH IgE levels in blood.

Question 21

What is Chronic Mucocutaneous Candidiasis?

Answer 21

Group of disorders that results in recurrent or persistent Candida infections (typically albicans) of the nails, skin and mucous membranes

Undefined T cell dysfunction

Question 22

A patient with recurring and sometimes persistent Candida infections of the skin, nails and mouth probably has what condition? What causes this?

Answer 22

Chronic Mucocutaneous Candidiasis

Some type of T cell dysfunction. Not understood.

Question 23

What is TAP-1 or TAP-2 Deficiency?

Answer 23

• Genetic deficiency of either TAP result in very low levels of MHC Class I because cannot load peptides
• Results in very low levels of CD8 T cells because these cells cannot pass positive selection in the thymus
• Highly susceptible to viral infections and some intracellular infections – Cannot produce a CTL response.

Also called: bare lymphocyte syndrome (MHC class I)

Question 24

What is CD8 alpha chain defect?

Answer 24

Lack of CD8 T cell

• Highly susceptible to viral infections and some intracellular infections – Cannot produce a CTL response.

Question 25

What is perforin deficiency?

Answer 25

• non-sense mutation of perforin.
• Normal CD8 T cell levels
• ineffective CTLs and NK cells
• highly susceptible to viral and some intracellular bacterial infections.

Question 26

Why do genetic defects that prevent CD4+ T cell effector functions result in SCID?

Answer 26

because B cell responses require effector T cell function

cell-mediated responses require effector T cell function too (Macs)

Question 27

What is Bare lymphocyte syndrome (classic MHC class II version)?

Answer 27

• lack expression of MHC class II molecules
• unable to mount acquired CD4+ T cells responses or acquired B cell responses

SCID

Question 28

What is Wiskott-Aldrich syndrome (WAS)?

Answer 28

• defect in cytoskeletal reorganization
• T cells reorganize their cytoskeleton so that they can deliver their effector molecules directly onto their target cell. This goes for both CD4+ and CD8+ T cells
• The defect in WAS causes a crosstalk deficiency that prevents proper cytokine signaling from effector T cells to B cells and macrophages.

SCID

Question 29

What is Adenosine deaminase (ADA) or Purine nucleotide phosphorylase deficiencies?

Answer 29

• result in accumulation of toxic nucleotide catabolites that kills all lymphocytes during their development
• these two deficiencies result in patients that have no B cells or T cells

SCID

Question 30

What is Common gamma chain deficiency?

Answer 30

• Deficiency of a component of several important cytokine receptors
• prevents signaling through each of those receptors
• receptor chain interacts with Jak3
• Because several of the cytokine receptors are critical for B and T cell development
  (IL-2 [T cell growth factor], IL-7 [B cell growth factor], etc)
  This deficiency results in SCID.

These patients have elevated B cells but are nonfunctional and few T cells or NK cells

Question 31

What is Janus kinase 3 (Jak3) deficiency?

Answer 31

Signaling from cytokine::receptor is disrupted

• Blocks B cell development (IL7)
• Blocks T cell development during activation (IL2)

SCID

No B cells and no effector T cells

Question 32

What is CD3 deficiency?

Answer 32

• results in a patient having no CD4+ or CD8+ T cells
• no T cell function: SCID. Deficiency can result from nonfunctional CD3 delta, epsilon, or zeta chain

Total lack of T cell function

SCID

Question 33

what is complete DiGeorge Syndrome?

Answer 33

• Along with the other maladies of DiGeorge, patient has no thymus or malfunctioning thymus
• High susceptibility to bacterial, fungal, and viral infections, including opportunistic pathogens.
• Treatment of athymia: Thymic transplant

SCID

Question 34

what is ZAP-70?

Answer 34

tyrosine kinase that associates with ITAMs during T cell receptor signaling

• Required for transduction of signals through the TCR

Question 35

What is ZAP-70 Deficiency?

Answer 35

Lack of this tyrosine kinase leads to absence of CD8 T cells and normal level of CD4 T cells, but these CD4 T cells are nonfunctional.

No functioning T cells = SCID

Tx is bone marrow transplant

Question 36

What is Omenn Syndrome?

Answer 36

SCID
- also autoimmune disease

• results from mis-sense mutations -> partially active RAG- genes
• no B cells and low numbers of T cells that are oligoclonal, and autoreactive
• susceptible to all types of infections
• suffer from autoimmune disease that is manifested in the skin and the intestinal tract
• —erythroderma, desquamation, alopecia, chronic diarrhea, FTT, lymphadenopathy, hepatosplenomegaly
• Only effective treatment is a bone marrow transplant.

Question 37

Mis-sense mutations that result in RAG- genes that are only partially active results in what disease?

Answer 37

Omenn Syndrome

Question 38

What is Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED)?

Answer 38

• genetic deficiency of the gene that encodes the autoimmune regulator (AIRE) that is expressed in the thymic medulla
• The purpose of this transcription factor is to drive expression of many host proteins that can be used as a source of self peptides for display on MHC class I and MHC class II during negative selection of T cells
• RESULTS in a myriad of autoimmune disorders such as:
• • polyglandular autoimmunity that results in underproduction of many hormones
• • total baldness (alopecia totalis)
• • malabsorption of intestines (diarrhea)
• • a number of other maladies

Question 39

What is AIRE?

Answer 39

Genes that act as autoimmune regulator in the thymic medulla

• provides self-peptides during negative selection of T cells

Question 40

What is Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked Syndrome (IPEX)

Answer 40

• genetic deficiency of FoxP3 expression by Tregs
• results in early onset (typically 1st year of life) autoimmunity manifested in a variety of tissues.
• Clinical presentation: clinical triad of
  1) watery diarrhea
  2) eczematous dermatitis
  3) endocrinopathy (type 1 diabetes)

Also typical to display:
Coomb’s positive anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy

Treatment: immunosuppression and/or bone marrow transplant

Question 41

A genetic deficiency of FoxP3 results in what disease? What is the typical presentation of this patient?

Answer 41

What is Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked Syndrome (IPEX)

clinical triad of

1) watery diarrhea
2) eczematous dermatitis
3) endocrinopathy (type 1 diabetes)

Question 42

What is Autoimmune Lymphoproliferative Syndrome (ALPS)?

Answer 42

• results from a mutation that results in no expression of functional Fas, Fas-ligand, or caspase 10
• Without any of these molecules, immune cells fail to undergo apoptotic death following an immune response, resulting in overpopulation of secondary lymphoid tissues
• characterized by lymphadenopathy and splenomegaly
• Clinical presentation: autoimmune hemolytic anemia and neutropenia, thrombocytopenia, lymphadenopathy, splenomegaly, and a large number of double-negative (CD4-/CD8-) T cells.

Treatment: immunosuppresion and IVIg

Question 43

A large number of double negative CD4 and CD8 T cells would indicate what disease? Why?

Answer 43

Autoimmune Lymphoproliferative Syndrome (ALPS)

CD4 and CD8 T cells cannot undergo apoptosis during development so persist as double negatives.

Question 44

In what deficiency would you see increased susceptibility to Giardia lamblia?

Answer 44

• IgA deficiency
• Giardia is a protozoal intestinal parasite often seen in selective IgA patients -> remember, IgA is the only Ab isotype efficiently transported into mucosal secretions
• Presumed that giardia needs attachment to colonize the GI tract

Question 45

Your patient presents with petechial hemorrhages due to small and poorly functional platelets. She also has clotting problems, including, nose bleeds that resolve poorly and bleeding gums. What is your tentative diagnosis?

Answer 45

• Wiskott- Aldrich Syndrome
• Some patients may also devo autoimmune conditions, typically directed at either RBCs (autoimmune hemolytic anemia) or platelets (idiopathic thrombocytopenic purpura)

Question 46

What is the difference between the baseline IgM and IgM during infection in CD40/CD40L deficiency and AID deficiency?

Answer 46

• CD40/CD40L: T cells cannot supply the second signal of activation to B cells, so no full B cell activation occurs. During an infection, the patient will produce significantly lower levels of pathogen-specific IgM than a normal patient would. The overall IgM concentrations are higher than normal though b/c 1) they tend to suffer from more infections than a normal patient, resulting in constant T-independent antigen-specific B cell pseudo activation (no germinal centers), and 2) they are constantly making IgM specific for T-independent antigens of normal flora pathogens (some of these antibodies cross-reactive with blood group antigen A or B antigens).
• In a patient with an AID deficiency, full B cell activation can occur, resulting in germinal center reactions and lots of B cell clonal expansion. Because no class switching can occur, all of the plasma that are produced are making IgM. These patients will make higher than normal amounts of IgM that are specific for a pathogen during an infection.