Immunodeficiency

Question

• Absent or defective CD18 is associated with which immunodeficiency? What cellular functions is CD18 required for?

Answer

• Most patients with LAD express no CD18, an essential β2-integrin on lymphocytes, macrophages, and neutrophils which is required for:1) Lymphocyte interactions with antigen-presenting cells (e.g., macrophages, dendritic cells)2) Leukocyte adhesion to endothelial cells, which is a necessary first step for leukocyte migration to sites of infection and inflammation3) Phagocytosis of bacteria opsonized with complement component C3b (specifically iC3b, a proteolytically inactive form of C3b capable of opsonization).

Q

• What sign generally causes doctors to suspect LAD (leukocyte adhesion deficiency) in newborns?

Answer

• Leukocyte adhesion deficiency (LAD) is a rare, primary immunodeficiency characterized by defective phagocytic cells and marked leukocytosis due to:A defective or absent integrin proteins on phagocytic cells (Type 1 LAD)

• An absence of ligand (sialyl Lewis X) for selectins (Type 2 LAD)• A WBC differential will reveal extremely elevated levels of

neutrophils (6-10x normal) because the marginated pool of neutrophils enters the bloodstream, and the defects in integrin, selectin, and/or sialyl Lewis X makes them unable to leave the blood vessels.

• LAD may be suspected when the umbilical cord fails to separate within the first few weeks of birth.

Q

• A male neonate has recurrent pneumonia and gingivitis. He is found to have a white count of 75,000 cells/mm3 and a defect in the LFA-1 integrin. What is his most likely diagnosis?

• ALeukocyte adhesion deficiency type I

• BChediaki-Higashi disease

• CSevere Combined Immunodeficiency

• DChronic granulomatous disease

• EJob's Syndrome

Answer

• Leukocyte adhesion deficiency presents in the neonatal period with recurrent bacterial infections. Some of the presenting infections may include:

• Omphalitis• Pneumonia• Gingivitis• Peritonitis

Q

• What are the Ig levels in X-linked agammaglobulinemia?

Answer

• When BTK is mutated, B cell precursors fail to develop into mature B lymphocytes. The absent or decreased levels of mature B cells leads to a plasma cell deficiency, which leads to an absence or decreased level of all classes of immunoglobulins. A lack of immunoglobulins increases susceptibility to bacterial infections and enteroviruses.

Q

• What is the genetic defect in Bruton’s agammaglobulinemia?

Answer

• Bruton's Agammaglobulinemia is an X-linked recessive disorder caused by a mutation in the Bruton tyrosine kinase (BTK) gene, leading to absent or defective BTK.

Q• A mother brings her 18-month-old son to the pediatrician because he has

had multiple bacterial infections. Laboratory work shows a decrease in his number of B cells. He is found to have a defect in his tyrosine kinase gene with an absence of all classes of immunoglobulins. What is the inheritance pattern of this disorder?

• AMitochondrial inheritance

• BAutosomal dominant

• CX-linked recessive

• DX-linked dominant

• EAutosomal recessive

Q

• What is histologically absent in lymph nodes and tonsils of a patient with Bruton’s agammaglobulinemia?

Answer • Bruton's Agammaglobulinemia is an X-linked recessive disorder

caused by a mutation in the Bruton tyrosine kinase (BTK) gene, leading to absent or defective BTK.Normally, the BTK tyrosine kinase functions in signal transduction during immunoglobulin maturation. Its absence results in a developmental block at the pre-B cell stage.

• When BTK is mutated, B cell precursors fail to develop into mature B lymphocytes. The absent or decreased levels of mature B cells leads to a plasma cell deficiency, which leads to an absence or decreased level of all classes of immunoglobulins. A lack of immunoglobulins increases susceptibility to bacterial infections and enteroviruses.

• All lymphoid organs that normally contain mature B cells (lymph nodes, tonsils, adenoids, Peyer’s patches, spleen) may be smaller.

• Germinal centers are histologically absent in lymphoid organs that normally house mature B cells.

Q

• At what age does Bruton agammaglobulinemia typically present and why?

Answer

• Bruton's agammaglobulinemia is usually diagnosed after ~ 6 months of age due to the age-related decline of maternal IgG.

• Children with Bruton's agammaglobulinemia present with recurrent:

• Bacterial infections (e.g., H. influenzae, S. pneumoniae, S. aureus)

• Enteroviral infections (e.g., coxsackievirus, polio)• Giardia lamblia infections

Q• An infant is brought to the pediatrician's office for evaluation of recurrent

fungal and viral infections. He is found to have failure of development of the 3rd and 4th pharyngeal arches, resulting in hypoplasia of the thymus and parathyroid glands. Deletion of genes on which of the following chromosomes is associated with this disease?

• AChromosome 11 and 22

• BChromosome 1

• CChromosome 11

• DChromosome 22

• EChromosome 2

Answer

• The patient has DiGeorge syndrome (thymic hypoplasia), which is a congenital T cell deficiency due to failure of development of the 3rd and 4th pharyngeal pouches. This failure results in hypoplasia of the thymus and parathyroid glands. Clinically, DiGeorge syndrome presents with recurrent fungal and viral infections. It is associated with a deletion of about 30-40 genes at location 11.2 on the long arm of chromosome 22. A deletion of genes on chromosome 2 is associated with chronic mucocutaneous candidiasis.

• DiGeorge anomaly craniofacial characteristics can result from teratogen (e.g. alcohol) exposure during weeks 4-6 of fetal development.

Q

• A high-risk neonate is found to have craniofacial abnormalities consistent with DiGeorge syndrome. FISH testing reveals normal-appearing chromosome 22. If a teratogen is responsible for this condition, during what period of embryogenesis did the exposure likely occur?

Answer

• DiGeorge anomaly craniofacial characteristics can result from teratogen (e.g. alcohol) exposure during weeks 4-6 of fetal development.

Q

• What is the inheritance pattern of interleukin 12 receptor deficiency?

Answer

• Interleukin 12 (IL-12) receptor deficiency is an autosomal recessive disorder.It is discovered in otherwise healthy patients with disseminated mycobacterial, fungal andsalmonella infections.

• IL-12 produced by dendritic cells and macrophages normally induces differentiation of naive T cells into Th1 cells. Therefore, IL-12 deficiency is characterized by reduced Th1 cell response.

• IL-12 receptor deficiency syndrome may present after administration of BCG (Bacillus Calmette–Guérin) vaccination.

Q

• The production of which interferon is most affected by IL-12 receptor deficiency?

Answer

• IL-12 receptor deficiency leads to decreased production of IFN-γ by Th1 cells and NK cells

Q

• What causes Hyper IgM syndrome?

Answer

• Hyper-IgM syndrome is characterized by the failure of antibodies to switch classes from IgM to IgA/IgG/IgE once an antigen is recognized.Hyper-IgM syndrome is caused by a defective CD40 ligand (CD40L, also called CD154) that is normally expressed on CD4+ T helper cells. B cells express CD40, and both CD40L and CD40 are necessary for class switching. CD4+ T helper cells are unable to induce B cells to undergo immunoglobulin class switch (from IgM to other classes).

• ~70% of patients have the X-linked form of the disease, while others inherit the disease in an autosomal recessive pattern.

Q

• What infections are most common in Hyper-IgM syndrome?

Answer

• Hyper-IgM syndrome is diagnosed with normal or elevated levels of IgM, extremely low levels of IgG and absent IgA/IgE. Typically, neutrophil count is also low. Hyper-IgM syndrome presents in infancy with recurrent pyogenic upper and lower respiratory infections because opsonizing IgG level is so low.

• Due to the defect in cell-mediated immunity, patients are susceptible to pneumonia caused by:

• Pneumocystis jiroveci• Cryptococcus• Cytomegalovirus

Q

• What are five clinical presentations of Hyper-IgE syndrome?

Answer

• To remember the features of Hyper-IgE syndrome, use the DRAFT mnemonic:

• Dermatologic problems (e.g., eczema, newborn rash, mucocutaneous candidiasis)

• Respiratory (sinus, lung) infections• Recurrent Abscesses (staphylococcal)• Coarse Facies• Two rows of Teeth (primary teeth are retained)