Chapter 2.3 Primary Immunodeficiency

Question 1

What is DiGeorge Syndrome?

What causes it?

Answer 1

developmental failure of the 3rd and 4th pharyngeal pouch

due to 22q11 microdeletion

Question 2

How do patients with DiGeorge Syndrome present?

Answer 2

T cell deficiency (bc lack of thymus)

Hypocalcemia (lack of parathyroids)

Abnormalities of heart, great vessels, and face

Question 3

What is SCID?

Answer 3

defective cell-mediated and humoral immunity

Question 4

What are the etiologies of SCID?

Answer 4

cytokine receptor defects
(CD4+ T cell helps B cell become mature and helps CD8+ T cell become activated..cytokines drive maturation of inflammatory state, if receptor defects, patients can develop SCID)

-Adenosine deaminase deficiency (enzyme necessary for deamination of adenosine and deoxyadenosine, buildup of adenosine and deoxyadenosine is toxic to lymphocytes)

MHC class II deficiency (recognized by CD4+ T cell which helps activate CD8+ and B cells, if CD4 cannot be activated then get defective function of B cells and CD8 cells)

Question 5

What are characteristics of SCID?

Answer 5

Don’t have T cells (so get fungal and viral infections)

Don’t have B cells (so get bacterial and protozal infections)

including opportunistic infections and live vaccines

Question 6

How do you treat patients with SCID?

Answer 6

• sterile isolation
• stem cell transplant

(take normal stem cells and put into SCID patient bone marrow, that HSC can generate normal B and T cells and develop normal immune response)

Question 7

Describe X-linked agammaglobulinemia. What causes it?

Answer 7

Complete lack of immunoglobulin (in the blood)

Due to disordered B-cell maturation because of mutated Bruton tyrosine kinase

Naive B cells cannot mature to plasma cells (plasma cells have ability to secrete Ig into blood, so cannot drop Ig into blood)

Question 8

How is X-linked agammaglobulinemia inherited?

Answer 8

X linked

due to mutated Bruton tyrosine kinase

(BTK is signaling molecule that is necessary for B cell to become plasma cell, when its mutated it results in X linked agammaglobulinemia)

Question 9

When does X-linked agammaglobulinemia present?

Answer 9

Presents after 6 months of life

baby has mom’s antibodies floating around prior to that

Question 10

What 3 types of infections are patients with X-linked agammaglobulinemia susceptible to? Why?

Answer 10

bacterial (don’t have ability to opsonize properly because no production of IgG)

enterovirus (virus that affects mucusoa surface of GI tract…IgA protects against mucosal infections but these patients don’t have IgA so they get enterovirus)

Giardia infections (usually prod. GI function, mucosal where IgA would have been protective against it)

Question 11

Can patients with X-linked agammaglobulinemia be given polio vaccine?

Answer 11

no, live vaccines (e.g. polio) must be avoided

cannot deal with attenuated live vaccine

Question 12

Describe CVID (Common variable Immunodeficiency disease).

What are patients at increased risk for? Why?

Answer 12

Low Ig due to B cell or helper T cell defects (B cells produce Ig and helper T cells prod IL4 and IL5 when appropriate signal is present)

Low Ig- so increased risk for bacterial, enterovirus, and Giardia infections

increased risk for autoimmune disease and lymphoma

Question 13

When does CVID usually present and what are patients at risk for?

Answer 13

usually presents in late childhood

increased risk for autoimmune disease and lymphoma

Low Ig- so increased risk for bacterial, enterovirus, and Giardia infections

Question 14

Describe IgA deficiency. What are patients at increased risk for?

Answer 14

Low serum and mucosal IgA

increased risk for mucosal infections, especially viral

Question 15

What is the most common Ig deficiency?

Answer 15

IgA deficiency

Question 16

In which GI disease do a high percentage of patients have IgA deficiency?

Answer 16

celiac disease

a component is IgA deficiency

Question 17

How is Hyper-IgM syndrome characterized?

Describe/review the two ways in which B cells can be activated.

Answer 17

elevated IgM

due to mutated CD40L or CD40 receptor

(2 ways by which B cells get activated… naive B cell expressing IgM on surface, antigen binds IgM and that results in IgM secreting plasma cell that can produce IgM… or B cell can internalize the antigen and present the antigen on MHC class II, then CD4+ T cell will bind antigen and that is first stimulus, second stimulus is CD40. CD40 expressed by B Cell and binds to CD40 receptor on T cell… that is second signal) when CD4+ T cell is activated it produces IL4 and IL5 which go back to hit B cell to cause it to mature and undergo class switching so that B cell can produce IgA, IgG, and IgE

Question 18

What will be the implications of a mutated CD40L or CD40 receptor?

Answer 18

(first way of activating naive B cell expressing IgM on surface, antigen binds IgM and that results in IgM secreting plasma cell that can produce IgM… is in tact)

Second signal cannot be delivered to helper T cells during B cell activation

Cytokines necessary for Ig class switching not produced

Low IgA (mucosal infections), IgG (recurrent pus formation), and IgE result in recurrent pyogenic infections, especially at mucosal sites

Question 19

What type of infections will a patient with Hyper IgM syndrome be susceptible to? Why?

Answer 19

Low IgA (mucosal infections)

Low IgG (recurrent pus formation)

and low IgE

Low IgA, IgG, and IgE result in recurrent pyogenic infections, especially at mucosal sites

Question 20

What triad characterizes Wiskott-Aldrich Syndrome?

Answer 20

thrombocytopenia (increased risk of bleeding, mucosal membrane bleeding and petechia on skin)

eczema

recurrent infections (defective humoral and cellular immunity)

Question 21

What causes Wiskott-Aldrich Syndrome? How is it inherited?

Answer 21

X linked

mutation in WASP gene

Question 22

What will patients with C5-C9 deficiency be at increased risk for?

Answer 22

C5-C9 deficiency -increase risk for Neisseria infection

Question 23

What will a C1 inhibitor deficiency lead to? Describe the mechanism.

What is the classical clinical finding?

Answer 23

C1 inhibitor deficiency - hereditary angioedema

Classical finding: characterized by edema (especially periorbital) and mucosal surfaces ….

C1 is important activator of complement and its important early protein in complement pathway, when activated it turns on complement… C1 inhibitor helps control C1…without this inhibitor get overactivation of C1, overactivation of complement, vasodilation, increased vascular permeability, classic findings of acute inflammation (edema)