1. IMMUNODEFICIENCY DIASEASES Tang Yongmin, MD Department of Hematology-oncology Children’s Hospital Zhejiang University School of Medicine

2. Immunodeficiency Diseases Definition: ID is a group of diseases resulting from defects in immune system including cell, molecules, constitutional structures as well as enzymes etc. resulting in a variety of clinical manifestations including infection, autoimmune diseases and hematopoietic malignancies. Primary: Secondary: Acquired:

3. Basic knowledge review Immune organs and cell components: central: BM, Thymus peripheral: spleen, tonsils, lymph nodes components: T, B, NK, monocytes/macrophages, nutrophils, complements Immune functions and reactions: specific:humural B-mediated cellular T-mediated non-specific: phagocytosis, natural barrier (skin, mucus membrane) Immune function disorders: high function:hypersensitivity low function:hyposensitivity no function:immunodeficiency

4. E Baso Totipotent stem cell Pluoripotent stem cell Lymphoid stem cell Pro-B Pro-T B CFU-G G T M CFU-GM CFU-M CFU-GEMM BFU-E BFU-Mk RBC P l t NK ? Normal hematopoiesis

5. CD 34 CD 7 T cell lineage differentiation CD 7 CD 71 CD 1 CD 4 CD 8 CD 7 CD 2 CD 3 CD 4 CD 2 CD 5 CD 7 CD 3 CD 8 CD 2 CD 5 CD 7 CD 3 CD 4 CD 2 CD 5 CD 7 CD 38 CD 3 CD 8 CD 2 CD 5 CD 7 CD 38 CD34 Stem cell Stage I II III Thymus BM Blood

6. B cell lineage differentiation CD 34CD34+/- CD 10 CD 19 CD 20 CD 22 CD 10 CD 19 CD 20 CD 21 CD 22 CD 24 C  CD 10 CD 20 CD 21 CD 22 CD 24 SmIg CD 38 CD 20 CD 21 CD 22 Stem cell Progenitor B Pre-pre-B Pre-B Mature B Plasma cell IgG IgM IgA IgD IgE CD 34 CD 19 CD 79 CyCD 22

7. Features of immune system in children Monocyte/macrophages: the antigen presenting ability in neonatal stage is not mature; neutrophils: transient reduction of function due to lack of chemotatic factors, opsonins in serum in neonatal stage; complements: cannot pass through placenta. Lower levels of complements in newborns than in adults. Premature babies are even lower; T cell and lymphokines: activation of T cells only can be induced by larger dose of antigens. Th number and the activities of the lymphokines are reduced while Ts number is reduced with higher activity. Th1 (IL-2, r-IFN, IL3, inhibit Ig production) activities increase with decreased activities of Th2(IL-3, IL-4, IL-5, activating B to produce Ig) in newborns;

8. Features of immune system in children (cont ’ ) B cell and their immunoglobulins: IgM: maternal IgM can not pass through the placenta due to its large molecule. Although IgM begins to be synthesized at very early stage (12 wks of gestation) of a fetus with limited amount, normal level of IgM in cord blood in newborns is very low. High levels of IgM in newborn’s blood indicate intrauterine infection, usually with E Coli. IgG: including IgG1, IgG2, IgG3 and IgG4. Maternal IgG can pass through placenta and the IgG in newborns is mainly derived from their mothers. The maternal IgG in newborns will disappear completely by 6th month of age. The IgG level of infant’s own begins to rise gradually after 3 month of age, therfore it reaches a nadir at the age of 3 ~ 4 month. IgA: fetus does not produce IgA and maternal IgA can not pass through placenta as well, which results in a very low levels of secretory IgA in both infants and young children.

9. Classification of Immunodeficiency Diseases Primary (PID): congenital, inherited (infants and children). Secondary (SID): malignancies, virus, malnutrition, medicines and radiation (any ages) etc. Acquired (AID): AIDS caused by HIV (any ages).

10. Classification of PID SPECIFIC MECHANISMS: Antibody deficiency: 1. transient hypoglobulinemia in infancy 2. X-linked agammaglobulinemia (Bruton’s diseases) 3. common variable agammaglobulinemia 4. selective IgA deficiency 5. X-linked immunodeficiency diseases with high levels of IgM 6. IgG subclass deficiency T cell deficiency: DiGeorge syndrome (congenital thymic hypoplasia) Nezelof syndrome (with abnormal synthesis of Ig) T, B combined immunodeficiency diseases: 1. SCID (including ADA deficiency, PNPdeficiency) 2. Wiscott-Aldrich syndrome 3. Ataxia-telangiectasia)

11. Classification of PID (continued) NON-SPECIFIC MECHANISMS: Complement defects: C1-4, C5-9 (Neisseria infection) Abnormality of phagocytosis: quantitative: neutrocytopenia qualitative: C3a and C5a deficiency Chediak-Higashi syndrome lazy leukocyte syndrome chronic granuloma disease (CGD) defects of adhesion molecules: iC3b receptor LFA-1 p150, 95 OTHERS: Hyper-IgE syndrome X-linked lymphoadenopathy syndrome

12. Clinical Manifestations Common: recurrent infections, autoimmune disorders, malignancies Specific features: B: pyogenic bacteria T: fungal and viral infections, autoimmune disorders and malignancies T, B: severe infections with early death phagocytic: suppurative infections, CGD complement: Neisseria infections

13. Diagnosis of PID Family history: congenital or inherital Clinical manifestations: recurrent infections, autoimmune disorders, malignancies (lymphoma etc.) Laboratory examinations: (see next)

14. Lab tests of PID Deficiencyscreening humoralserum protein electrophoresis Ig quantitation isoagglutinin titration cellularlymphocyte counting X-ray thymus shadow skin tests(OT or PPD) PHA, SK-SD phagocyticWBC counting and differential morphology complementstotal C activity (CH50) C3 quantitation Further examinations immunoelectrophoresis circulating B cell count tissue biopsy Lateral X-ray of pharynx gene diagnosis T cell and subsets transformation assay tissue biopsy lymphokine determination gene diagnosis chemotatic assay adhesion tests phagocytosis assay NBT, spleen scanning other complement determination opsonin determination

15. Features of individual PID Antibody deficiency: 1. transient hypoglobulinemia in infants 2. X-linked aggamaglobulinemia (Bruton’s diseases) 3. common variable aggamaglobulinemia 4. selective IgA deficiency 5. X-linked immunodeficiency diseases with high levels of IgM 6. IgG subclass deficiency T cell deficiency: DiGeorge syndrome Nezelof syndrome T, B combined immunodeficiency diseases: 1. SCID (including ADA deficiency) 2. Wiscott-Aldrich syndrome 3. Ataxia-telangiectasia)

16. 月 0 0.5 1 2 3 岁 1. Infantile transient hypoglobulinemia

17. 2. X-linked aggamaglobulinemia (Bruton’s diseases) 0 0.5 1 2 3 4 5 岁

18. 4. selective IgA deficiency 病人 正常人

19. 6. IgG subclass deficiency Normal IgG subclasses Patient with IgG1 deficiency

20. 3rd pharyngeal pouch 4 th pharyngeal pouch 2nd pharyngeal pouch 1st pharyngeal pouch Thymus dysplasia Parathyloid gland dysplasia Cellular ID Facial dysmorphism Cardiovascular abnormalities Hypocalcemic tetany or convulsion DiGeorge syndrome

21. SCID: e.g. ADA deficiency Pro-BPro-T B T Pro-B Pro-T B T Lymphoid stem cells ADA+ADA- Normal SCID

22. Treatment of PID General : nursing, prevention of infection, vaccination in dead vaccines Replacement: r-globulin, fresh plasma, RBCs, WBCs; cytokines including thymosin, transfer factor, IL-2 etc.; CAUTION: (1) T deficiency: radiate blood before transfusion to prevent GVHR. (2) Selective IgA deficiency: patients can not receive IgA from any source duo to the possibility of anti- IgA antibody in the body of the patients Reconstitution of immune function: BMT, fetal liver, thymus epithelium transplantation, gene therapy etc.

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