Immunodeficit

1. Immunodeficit Deficit di uno o pi� elementi del sistema immunitario che si manifesta con aumentata suscettibilit� alle infezioni (Infezioni ricorrenti). Immunodeficit Congeniti Acquisiti Immunodeficit A prevalente compromissione dei linfociti T A prevalente compromissione dei linfociti B Combinati Dei fagociti Del Complemento

2. Dei linfociti T Sindrome di Di George Dei linfociti B Agammaglobulinemia di Bruton Ipogammaglobulinemia variabile comune (CVI) Deficit selettivo di IgA Ipogammaglobulinemia con iper-IgM Combinati � Severe Combined ImmuneDeficiency (SCID) Disgenesia Reticolare (assenza di linfociti, monociti e granulociti) SCID di tipo svizzero (assenza di linfociti) ADA-SCID (assenza di linfociti T e B) SCID X-linked (assenza di linfociti T)

3. The case of Dennis Fawcett: a failure of T-cell help He was referred to the Children's Hospital with a sever acute infection of the ethmoid sinuses (Ethmoiditis). He had had recurrent sinus infections since he was 1 year old and pneumonia from an infection with Pneumocystis carinii when he was 3 years old. These infections were treated successfully with antibiotics. The physicians expected that he would have a brisk rise in his white blood cell count. But his white blood cell count was 4200 �l-1 (normal count 5000-9000 �l-1), 26% neutrophils, 56% lymphocytes, and 28% monocytes.

4. Seven days after admission to the hospital, his serum was tested for antibodies to streptolysin O, an antigen secreted by streptococci. No antibodies to the streptococcal antigen were found The IgG level was 25 mg/dl-1 (normal 600-1500 mg/dl-1), IgA was undetectable (normal 150-225 mg/dl-1) and his IgM level was elevated at 210 mg/dl-1 (normal 75-150 mg/dl-1) A lymph-node biopsy showed poorly organized structures with an absence of secondary follicles and germinal centers.

6. Dennis was given a booster injection of diphtheria toxoid, pertussis, tetanus toxoid (DPT) and typhoid vaccine. 14 days later no antibody was detected to tetanus toxoid nor to typhoid O and H antigens. Dennis had red blood cells of group O. His anti-A and anti-B antibodies were of the IgM class only.

7. His peripheral blood lymphocytes were examined by FACS analysis and normal results were obtained: 11% reacted with an antibody to CD19 87% with anti-CD3 2% with anti-CD56 His B cells (CD19+) had surface IgM and IgD and none were found with surface IgG or IgA. His activated T cells did not bind soluble CD40.

8. Dennis had a brother and sister. They were both well. There was no family history of unusual susceptibility to infection. Dennis was treated with intravenous gamma globulin and subsequently remained free of infection.

9. Hyper IgM Immunodeficiency (HIM) Is a rare primary immunodeficiency characterized by the production of normal to increased amounts of IgM antibody and an inability to produce sufficient quantities of IgG, IgA and IgE. Individuals with HIM are susceptible to recurrent bacterial infections and are at an increased risk of autoimmune disorders and cancer at an early age.

10. In the most common form of HIM there is a defect in the gene TNFSF5, found on chromosome X at q26. This gene normally encodes for CD40 ligand (CD154), a protein on T cells which binds to the CD40 receptor on B and other immune cells (macrophages, dendritic cells, mast cells)

12. The HIM is inherited as an X-linked recessive trait, and usually found only in boys. Sons of carriers have a 50% risk of inheriting the abnormal gene from their mothers. Daughters of carriers have a 50% risk of being carriers. 30% of cases of XHIM arise as �new mutations� and in these cases there is no previous history of the disorder in the family.

13. Males with a defect in the CD40 ligand gene: 1) isotype switching fails to occur 2) the initial activation and expansion of T cells in response to protein antigens is greatly reduced 3) the activation of macrophages is reduced

14. Males with a hereditary deficiency of the CD40 ligand exhibit consequences of a defect in both humoral and cell-mediated immunity. 1) Defects in antibody synthesis result in susceptibility to the pyogenic infections (es Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus). 2) Defects in cellular immunity result in susceptibility to opportunistic infections (bacteria, viruses, and fungi). DENNIS REVEALED SUSCEPTIBILITY TO BOTH KINDS OF INFECTION

15. MALES WITH A CD40 LIGAND DEFICIENCY CAN MAKE IgM IN RESPONSE TO T-CELL INDEPENDENT ANTIGENS

16. MALES MAY BECOME PROFOUNDLY DEFICIENT IN NEUTROPHILS, AND THIS IS A VERY PROMINENT FEATURE OF THEIR DISEASE WHY ? THE INTERACTION OF THE CD40 LIGAND WITH CD40 ON MACROPHAGES IS REQUIRED FOR THE SECRETION OF GM-CSF BY MACROPHAGES

17. Most patients with the X-linked Hyper IgM (XHIGM) syndrome develop clinical symptoms during their first year or second year of life. Symptoms include recurring upper and lower respiratory infections within the first year of life. Other signs include enlarged tonsils ,liver, and spleen, chronic diarrhea, and an increased risk of unusual or "opportunistic" infections (Pneumocystis carinii and Cryptosporidium). Neutropenia.

18. Treatment Regular infusions of IgG. Prophylactic treatment for Pneumocystis Carinii pneumonia. Patients with persistent neutropenia may also respond to granulocyte colony stimulating factor (G-CSF) therapy. Bone marrow transplantation or cord blood stem cell transplantation has been advocated in recent years.

19. DISCUSSION and QUESTIONS Why had Dennis no difficulty in isotype switching from IgM to IgD ? There is no DNA switch region 5� to the Cd gene. A single transcript of VDJC�Cd is alternatively spliced to yield the � or d heavy chain. Why did he make antibodies to blood group A and B antigens ? The blood group antigens are sugar groups can activate B cells in the absense of T cell help.

20. An autosomal recessive form of hyper-IgM syndrome has recently been identified, is much rarer and affects both sexes. This syndrome is due to mutations of the gene encoding a protein, the activation-induced cytidine deaminase (AID) expressed in B cells and required for their terminal differentiation.