Immunology

Question 1

Epidermal growth factor (EGF)

Answer 1

produced by keratinocytes and macrophages and is mitogenic for epithelial cells, hepatocytes, and fibroblasts

Question 2

Hepatocyte growth factor (HGF)

Answer 2

produced by fibroblasts, endothelial cells, and liver non-parenchymal cells and is mitogenic for epithelial cells

Question 3

Vascular endothelial growth facter (VEGF)

Answer 3

A family of 4 peptides (A-D)
Induces vasculogenesis in embryonic development
Induces angiogenesis in adults (tumors, chronic inflammation, and wound healing)
Produced by mesenchymal cells
Mitogenic for endothelial cells

Question 4

Platelet derived growth factor (PDGF)

Answer 4

Two chained molecule, 5 isoforms
Produced by platelets, macrophages, endothelial cells, and smooth muscle
Mitogenic for fibroblasts, smooth muscle cells, and monocytes

Question 5

Fibroblast growth factor (FGF)

Answer 5

Family of growth factors with 10 members
Angiogenesis
Macrophage, fibroblast and endothelial cell migration
Muscle development
Hematopoiesis

Question 6

Transforming growth factor (TGF)-

Answer 6

Two chain protein with three isoforms
Post-translationally modified
Produced by platelets, endothelial cells, lymphocytes, and macrophages
Inhibits endothelial and lymphocyte growth
Stimulates fibroblast growth

Question 7

defects of innate immunity

Answer 7

complement deficiency
neutrophil defects
defects of IL-12/INF-gamma axis
defects of TLR signaling

Question 8

Wiskott Aldrich Syndrome

Answer 8

X-linked disease with characteristic triad:
Thrombocytopenia (small platelets)
Atopic Dermatitis (Eczema)
Immune deficiency (T and B cell defects)
Susceptibility to lymphoma and leukemia
Some WASP mutations also cause X-linked Thrombocytopenia (XLT) without other WAS features
WASP gain of function mutation causes severe congenital neutropenia

Question 9

Chediak-Higashi syndrome

Answer 9

Defects in the fusion of phagosomes with lysosomes

caused by defects in a gene whose product is involved in intracellular vesicle formation. Phagocytes in these
patients have impaired intracellular killing. Individuals with this syndrome also have other abnormalities
(partial albinism, abnormal platelet function).

Neutropenia
Partial oculocutaneous albinism
progressive neurologic abnormalities
mild coagulation defects
lymphoma-like accelerated phase (secondary to poor/absent NK cell function and inability to control EBV)
Lyst mutation (function not well known yet)

Giant granules in the cytoplasm of neutrophils are formed by the inappropriate fusion of lysosomes and endosomes.

Question 10

: Leukocyte adhesion deficiency-1 (LAD-1)

Answer 10

Defects in leukocyte recruitment to the site of infection

due to lack of the CD11a β2 integrin subunit that is required for expression of leukocyte integrins
including LFA-1. As a result, leukocytes are deficient in their ability to interact with other cell types
using LFA-1-mediated adhesion. The principal clinical manifestation is recurrent bacterial and fungal
infections, due to the inability of leukocytes to be effectively recruited to sites of inflammation. A related
form of this disease, LAD-2, results from a deficiency in enzymes required to generate the
carbohydrate ligands for endothelial selectins expressed on leukocytes, which are known to be
required for the recruitment of cells to sites of inflammation.

Question 11

Chronic granulomatous disease (CGD)

Answer 11

Defects in respiratory burst

may be caused by distinct genetic defects, affecting any one of 4 out of 5 subunits of the NADPH oxidase system, resulting in the
inability to produce the superoxide radical. Patients with this disease suffer from chronic bacterial
infections, which in some cases leads to the formation of granulomas. Deficiencies in other enzymes,
including glucose-6-phosphate dehydrogenase and myeloperoxidase, also impair intracellular killing
and lead to a similar but less severe phenotype.

Question 12

Defects in complement activation

Answer 12

Defects in the early components of the classical pathway predominantly affect the processing of immune complexes and the clearance of apoptotic cells, leading to immune complex disease. Deficiency of mannose-binding lectin (MBL), the recognition
molecule of the mannose binding lectin pathway, is associated with bacterial infections, mainly in early
childhood. Defects in the early components of the alternative pathway and in C3 lead to susceptibility
to extracellular pathogens, particularly pyogenic bacteria. Defects in the membrane attack
components are associated only with susceptibility to strains of Neisseria species, the causative
agents of meningitis and gonorrhea, implying that the effector pathway is important chiefly in defense
against these organisms.

Question 13

X-linked agammaglobulinemia (XLA)

Answer 13

This disease is characterized by a severe reduction in B cell numbers, due to a defect in the Brutonʼs tyrosine kinase (Btk) that is known to play a critical role in
BCR-mediated signaling events necessary for B cell development.

Characterized by defect in B cell development, (absent B cells, lymph nodes and tonsils)
Recurrent infections by pyogenic encapsulated bacteria (S. pneum, H. inf, S. aureus, Pseud.)
Susceptible to enteroviral meningoencephalitis
Defect in cytoplasmic tyrosine kinase called Bruton’s Tyrosine Kinase (BTK)

treatment
IgG replacement therapy intravenously (IVIG) every 3-4 weeks or subcutaneously every 1-2 weeks

No significant infections after IVIG

Question 14

Selective IgA deficiency

Answer 14

Defects in the synthesis of select immunoglobulin isotypes

the most common inherited form of immunoglobulin deficiency (1/500 individuals are affected) and is associated with mild enhancement of susceptibility to lung infections

Development of anti-IgA antibodies may lead to severe anaphylactic reactions with blood transfusions
Low switched memory B cells associated with pneumonia, bronchiectasis and autoimmune diseases
In vitro, IL-21 can induce IgA synthesis in IgAD pts

Question 15

common variable immunodeficiency (CVID)

Answer 15

IgG and IgA synthesis are usually defective, with normal or slightly reduced numbers of B cells. The genetic defects involved are diverse (i.e., mutations in CD19, BAFFR, TACI, ICOS).

CVID is characterized by:
Reduced serum levels of IgG, IgA and/or IgM
Reduced or absent isohemagglutinins and/or poor response to vaccines
Patient older than 2 years of age
All other causes of immune deficiency ruled out

Peak onset usually in 2nd or 3rd decade of life
Slow decline in all classes of immunoglobulin
Immunodeficiency evolves over time
Recurrent sinopulmonary infections (usually bacterial in origin)
Granuloma formation in lungs and liver
Autoimmune, gastrointestinal, endocrine, and hematologic disorders can be associated

Mutations found in TACI in 10-15% CVID
6 TACI mutations identified
CVID, IgAD and healthy individuals found in members of the same family with same mutation
Some heterozygous (Autosomal Dominant)
Some homozygous mutations
No genotype-phenotype correlations found
? other factors affect expression of disease (MHC molecules)

Question 16

Hyper-IgM syndrome:

Answer 16

This X-linked disease is caused by a defect in CD40L expression and/or 
structure. CD40L plays an important role in both T-B and T-macrophage interactions, where it is 
involved in regulation of Ig-class switching, germinal center formation and macrophage activation. As a 
result, patients with hyper-IgM have deficiencies in both humoral and cell-mediated immune response. 
The disease is designated “hyper-IgM” because in the absence of CD40L B cells are unable to 
undergo Ig-class switching from IgM to any of the other Ig isotypes. 

Patients susceptible to:
Recurrent sinopulmonary and opportunistic infections, neutropenia, parvovirus-induced bone marrow suppression, and cancer
Characterized by a failure of B cells to undergo immunoglobulin isotype switching from IgM/IgD to other Ig isotypes

Low or undetectable serum levels of IgG, IgA and IgE with normal or elevated IgM
Synthesize specific IgM antibody titers but no IgG antibodies and lack memory responses
We and four other groups identified the cause of X-HIM as a defect in the CD40 ligand gene resulting in a failure of interaction between CD40 ligand on T cells and CD40 on B cells, monocytes and other cells

Question 17

DiGeorge syndrome

Answer 17

Defective thymus development

caused by defective development of thymic
epithelium, hence defective T cell development. Severity is highly variable, and many affected
individuals eventually generate normal T cell numbers and immune responsiveness. Patients with
DiGeorge syndrome may show a variety of other symptoms due to defective development of the
parathyroid glands and other structures that develop from the third and fourth pharyngeal pouches
during fetal life. This disorder has been instrumental in establishing the role of the thymus for T cell
development.

Defect in embryogenesis, 3rd and 4th pharyngeal pouches
Most common genetic defect: deletion of 22Q11, mutation in T box-1 (TBX1)
Clinical features:
Dysmorphic facies (micrognatia)
Hypocalcemia (lack of parathyroids)
Depressed T-cell immunity (absent thymus)
Congenital heart disease
Presents in first few days of life (tetany)
Diagnosed immediately by lateral chest x-ray (absence of thymic shadow)

Question 18

bare lymphocyte syndrome

Answer 18

characterized by a nearly
complete loss of MHC class II gene expression on professional APC. It is caused by the loss of one or
more transcription factors required for MHC class II expression. As a result, no MHC class II molecules
can be expressed on thymic APCs and thymic epithelial cells and development of CD4 T cells is
abrogated.

Secondary to absent MHC class II, class I or both
Class II deficiency affects CD4 T cells
Class I deficiency affects CD8 T cells
In contrast to mice, humans have some T cell development but no T cell function because of absence of MHC molecules to present antigen

Question 19

Omenn’s Syndrome

Answer 19

Defects in VDJ recombination:

SCID variant caused by hypomorphic mutation in any SCID causing gene (RAG-1, RAG-2 etc..)
Restricted TCR heterogeneity
Autoreactive T cells, dermatitis, skin infections, lymphadenopathy

: Individuals with defects in the RAG-1 or RAG-2 genes have defective
VDJ recombination and lack B and T cells, resulting in SCID. Some individuals with RAG mutations
still have residual RAG activity, leading to abnormally activated T cells

Question 20

severe combined immunodeficiencies (SCID)

Answer 20

Defects that affect both cell-mediated and humoral immune responses: Because T cells play a central
role in adaptive immune responses, T cell defects may be sufficient to cause abnormalities in both cell-mediated and humoral immunity. Individuals with severe defects in adaptive immune responses suffer from life-threatening infections during the first year of life and will die in the absence of treatment

Question 21

X-linked SCID (X-SCID)

Answer 21

Defects in cytokine signals that are important for T cell development:

caused by mutations in an X-linked gene encoding the common γ chain (termed γc), shared by the
receptors for IL-2, -4, -7, -9, and -15. Since IL-7 is required for lymphocyte development, X-linked
SCID patients are defective in the development of lymphocytes.

Question 22

Adenosine deaminase (ADA) deficiency and purine nucleotide phosphorylase (PNP) deficiency

Answer 22

result in SCID due to accumulation of nucleotide metabolites that are particularly toxic to developing T cells (and B cells).

Question 23

Defects in T cell signaling

Answer 23

There are a large number of rare immunodeficiencies that effect either the expression of the TCR/CD3 complex or a component of the T cell activation signal transduction cascade (e.g. ZAP70, Lck). In many cases, the exact genetic mutation has not been definitively identified

Question 24

Therapeutic approaches for congenital immunodeficiencies

Answer 24

Enzyme replacement therapy
Passive immunization
Bone marrow transplantation (BMT)
Gene therapy