Immunodeficiencies and antibody deficiences Flashcards
Normal B cell maturation & the role of Btk
An initial step in developing a functional B cell receptor occurs after the
μ heavy chain binds with surrogate light chains This complex is transported to the cell surface, where it is transiently
expressed This process generates a signal that results in rearrangement of light
chain genes. These light chains associate with existing μ heavy chains,
followed by binding to Igα and Igβ Btk (Bruton’s tyrosine kinase) is a cytoplasmic enzyme that is
expressed at all stages of B cell development
Btk is required for both pre-B-cell expansion and for mature B-cell survival and activation. Signaling through the pre-B-cell receptor (Pre-BCR) and B-cell antigen receptor (BCR) controls these developmental transitions. Btk is essential for maintenance of the sustained calcium signal following BCR engagement Disruption of BCR expression mature B-cell death
In Btk-deficient cells, these respective cell populations fail to
proliferate and instead undergo apoptotic death.
X-linked agammaglobulinemia (XLA)
Patients are asymptomatic at birth, onset of infections between 4-12 months of age.
o Infections pyogenic encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus,
Pseudomonas species)
These organisms account for most
septic infections
o Chronic sinusitis is most common infection
Profound deficiency of all immunoglobulins, mature B cells and plasma
cells
Incidence 1/100,000-200,000
Inheritance is X-linked recessive
Absence of Btk enzyme (Bruton’s tyrosine kinase)
Physical exam: Absence of tonsils
The earliest and most severe consequence of the XLA defect occurs at the pre-B-cell transition. Cytoplasmic μ is seen but markedly reduced numbers of surface IgM+ B cells in the bone marrow. These cells have
reduced proliferative capacity.
Circulating B cells in XLA have an “immature” phenotype
High expression of surface IgM and costimulatory CD38
Female carriers have B cells that express only the normal X chromosome. B cells expressing the abnormal B chromosome fail to
mature.
Tx XLA
IVIG
Additional defects causing Agammaglobulinemia and Hypogammaglobulinemia
Deletions of gene encoding IgG γ1, 2, 3, 4 and α1 or 2, ε cause deficiencies of individual classes or subclasses of immunoglobulins but circulating B cells are
present and overall antibody function is usually normal. Deficiency of CD19
described May 2006. (NEJM) B lymphocytes are present but respond poorly to antigens. Truncations are critical to signal transduction through CD19. No
abnormality in differentiation seen but memory B cells decreased.
Common variable immunodeficiency
May present at any age: From infancy to adulthood
Etiology unknown
Increased incidence of autoimmunity
Clinical features and treatment similar to Bruton’s
agammaglobulinemia
Hyper IgM immunodeficiency
Antibody deficiency characterized by low levels of IgG and IgA
Normal or elevated IgM levels
o Patients present in early infancy with upper and lower respiratory
infections
o Protracted diarrhea
o 50% of patients have persistent or cyclic neutropenia
o Liver disease is common
o Susceptibility to liver, biliary tract & GI tumors o CNS involvement (enteroviral meningoencephalitis)
x-linked hyper IgM
X-linked: Due to mutations of a T-cell ligand, CD40L
Features that suggest that the abnormality is secondary to an intrinsic
T lymphocyte defect.
o Susceptibility to Pneumocystis carinii & Cryptosporidium parvum
o Immunization with T dependent antigens does not result in switch
from IgM to IgG synthesis.
Treatment
IVIG Prophylaxis for Pneumocystis carinii GCSF treatment for those with neutropenia
Only 40% survive
Autosomal recessive Hyper IgM:
- Activation Induced Cytidine Deaminase (AID) an enzyme involved
in isotype switching
2.Defective CD40
- Sporadic patients intrinsic B cell defect with complete lack of class
switch recombination and somatic hypermutation (SHM) Mutations of the uracil-DNA glycosylase (UNG) recently described ? defects in CD40 signaling pathway
physiologic hypogammaglobulnemia
Normal physiologic nadir of IgG
Decline of maternal immunoglobulin
Prior to significant immunoglobulin production by the infant
transient hypogammaglobulinemia
Nadir of IgG more prolonged than physiologic hypogammaglobulinemia
(up to 3 years) Distinguished from physiologic hypogammaglobulinemia in that antibody
production to immunizations not seen Some evolve to IgA deficiency Infections seen in only 50%, others detected because related to patients
with other disorders
IgA deficiency
Most common humoral deficiency
As frequent as 1/200 in some ethnic groups
Sino-pulmonary infections
Some develop IgE anti IgA antibodies and are at risk of anaphylactic
reactions when infused with intravenous IgG (IVIG). Etiology unknown
Tx of antibody deficiency
Gamma globulin Antibiotics ?Metronidazole (for protozoal intestinal infections)
Neutropenia
Cyclic:Autosomal dominant
21 day oscillations Infections ELA2 mutations (neutrophil elastase) Steroid therapy
Severe (Kostman’s): G-CSF receptor mutations in some
Bone marrow arrest at promyelocyte stage Treatment: G-CSF
Stem-cell transplantation
Leukocyte adhesion deficiency
LAD-1: CD18 common chain mutations
Present with recurrent severe (necrotizing infections), impaired pus formation & impaired wound healing Autosomal recessive
Severe phenotype <1% CD18 expression (death by 10 yrs)
o Infections begin in early infancy
o Recurrent infections of skin, soft tissues, respiratory tract, GI tract,
periodontal , delayed separation of umbilical cord (>30 days) o G- enteric bacteria, S. aureus, Candida sp, Aspergillus sp. o Impaired wound healing o Destructive gingivitis o Leukocytosis (no neutrophil margination on vascular walls) *
Neutrophils fail to migrate to sites of infection
o Impaired phagocytosis o Abscesses never form o Delayed separation of umbilical cord/ omphalitis o Necrotizing skin infections
Moderate phenotype: 1-10% CD18 expression (may live 40+ yrs)
Lab evaluation for LAD
o Decreased or absent CD11/CD18 expression
o Mutations of CD18
o Defective chemotaxis
o Impaired phagocytosis
o Abnormal T cell cytotoxity & NK activity
