Final Case Study

1. Final Case Study Case 6 Manzhu Kang, Phil Soto, Ivana Olguin California State University, Los Angeles

2. Case Summary • Clinical manifestations: • Recurrent Pneumonia, otitis media, erysipelas since 2 years old. • Atelectasis, chronic cough, no visible tonsil, moist crackles at both lung bases at age of 9. • Lab Results: • Very low level of IgG and IgM, no IgA, normal white blood cell count • Family History: • 2 brothers of his mother died from pneumonia at age of 2, but 2 healthy sisters who have a healthy son and daughter • One younger sibling with similar symptoms

3. Key Information Pointing to Diagnosis • Recurrent infections since age of 2 • Very low level of serum immunoglobulins • Absent tonsils • Family history

4. The Diagnosis X-linked Agammaglobulinemia

5. Diagnostic Tests • Immunoelectrophoresis reveals the absence immunoglobulin in serum • B cells level in the peripheral blood by flow cytometry with no or very little B cells • Genetic testing to detect mutation in X-chromosome

6. Immunoelectrophoresis

7. Therapy • Immunoglobulin replacement by weekly subcutaneous injection or intravenous infusion every 2-4 weeks, for life.   • Chronic prophylactic antibiotics are used in some centers for prevention of secondary complications (Howard, et al. 2006).

8. Prognosis • When intravenous gammaglobulin became available, the incidence of chronic enteroviral infection has markedly decreased in individuals with XLA. • As a result of earlier diagnosis, more liberal use of antibiotics, and the development of preparations of gammaglobulin that allow normal concentrations of serum IgG to be achieved, most individuals lead a normal life and may live well into their fifties (Howard, et al. 2006).

9. Communication of diagnosis and disease to the patient • Your results show that you have a genetic disease called x-linked agammaglobulinemia. It primarily affects boys that's why you and your brother are so sick all the time .The disease causes you to be unable to produce antibodies that make up gamma globulins in your blood. • This inherited disease caused you to become very sick since you were unable to fight off infections. Luckily, we have medicine that can make you better and only involves one shot every two to four weeks,Do you have any questions?

10. The Theoretical Immunological Basis for XLA • Btk is a protein expressed in B cell development which is involved in signal transduction and is involved in signaling the development of B cells if they are able to transiently express the heavy chain and light chain in the cell. • A defect in Btkwould cause B cell development to be incomplete and stopped at the pre-B cell step • Without maturation, B cells are not differentiated or sent to the lymph nodes which results in the lack of tonsils • When B cells mature they become plasma cell and release antibodies which have multiple functions • Antibodies can be involved in opsonization, neutralization, activating complement and blocking bacteria from attaching to epithelial cells

11. Expression of Fcg and complement receptors in monocytes ofX-linked agammaglobulinaemia and common variableimmunodeficiency patientsAmoras, A et al. (2007). Clinical & Experimental Immunology, 150(3), 422-428 • The objective was to investigate whether or not the alterations in the phagocytosis of monocytes in XLA patients was due to number of complement and Fcg receptors • Patients with XLA, CVI and healthy patients’ monocytes were analyzed by flow cytometry for complement receptors and Fcg receptors • CVI is a disease which prevents B cell differentiation and ability to produce antibodies but B cells are at normal levels • Found that XLA patients show the same or higher percentage of monocytes expressing Fcɤ and CR receptors • Findings support idea the inefficient chemotaxisand phagocytosis in XLA patients are not due to deficient receptors but rather defects in cytoplasmic transduction mechanisms, a result of the Btk defect

12. Flow cytometry of monocytes and relative fluoresence of complement and Fcɤreceptors Critiques: The sample size is small and all patients are on immunoglobulin therapy which could possibly result in an increase in expression of receptors

13. Take Home Messages • X-linked agamaglobulinemiaresults from a defect in Btk which causes a signal transduction defect that does not allow B cells to develop past the pre-B cell stage resulting in no antibody production • Typical symptoms are recurrent pyogenicinfections, ear infections, lung infections after infancy(nursing), missing tonsils, missing adenoids, pneumonia • No way to cure at this time, lifelong injection of immunoglobulins • With the development of immunoglobulin therapy it is possible to live a normal life

14. References • Moschese, V., Orlandi, P., Di Matteo, G., Chini, L., Carsetti, R., Di Cesare, S., et al. (2004). Insight into B cell development and differentiation. Acta Paediatrica, 9348-51. Retrieved from Academic Search Premier database. • Amoras, A., da Silva, M., Zollner, R., Kanegane, H., Miyawaki, T., & Vilela, M. (2007). Expression of Fcγ and complement receptors in monocytes of X-linked agammaglobulinaemia and common variable immunodeficiency patients. Clinical & Experimental Immunology, 150(3), 422-428. doi:10.1111/j.1365-2249.2007.03512.x. • Howard V, Greene JM, Pahwa S, Winkelstein JA, Boyle JM, Kocak M, Conley ME. The health status and quality of life of adults with X-linked agammaglobulinemia. Clin Immunol. 2006; 118: 201–8.  [PubMed]