#43 Immunodeficiencies II

1. #43 Immunodeficiencies II Immunology 297 September 9, 2015 Ikuo Tsunoda, MD, Ph.D. Department of Microbiology and Immunology LSUHSC E-mail: itsunoda@hotmail.com Homepage: http://tsunodalaboratory.web.fc2.com/

4. Thymic defects with additional congenital anormalies (Table 2.3a) • Failure of thymus to undergo normal development affects the development of all populations of T cells • DiGeorge syndrome, described by Dr. Angelio DiGeroge in 1968 • Deletion of region on chromosome 22 q11.2 can result in complete absence of a thymus: can be explained by a deletion of a transcription factor, T box-1 (TBOX1) • The result is immunodeficiency, nearly complete T cell defect, and lack of T cell-dependent B cell activation • Normal level of serum immunoglobulin • Defective development of structures that develop from the third and fourth pharyngeal pouches during fetal life: absent parathyroid glands, abnormal development of great vessels

5. Pharyngeal Pouches https://www.youtube.com/watch?v=WiE7LJu3AL4

6. Pharyngeal pouches. paired evaginations of embryonic pharyngeal endoderm, between the pharyngeal arches, extending toward the corresponding ectodermally lined pharyngeal grooves; during development they evolve into epithelial tissues and organs, such as thymus and thyroid glands. SYN: branchial pouches, endodermal pouches.

7. DiGeorge syndrome • 22q11.2 deletion syndrome = velocardiofacial syndrome = DiGeorge syndrome Microdeletion; a submicroscopic loss of a segment of DNA of varying size, typically several kilobases long • Incidence; 1 in 2000 - 4000 live births • Craniofacial and cardiovascular anomalies, immunodeficiency, short stature and hypocalcaemia • Cognitive and behavioral impairments and a high risk for developing schizophrenia • Mouse models of the 22q11.2 microdeletion Mouse chromosome 16

8. DiGeorge syndrome • Also can result in facial abnormalities including dysplasia of ears and mouth, and abnormally long distance between the eyes. Differing phenotypes occur because the mutation can (but does not always) affect the development of multiple organs: thymus parathyroid gland heart outflow vessels facial deformity CATCH 22 syndrome: cardiac, abnormal faces, thymichypoplasia, cleft palate, hypocalcemia

10. Immune disorders involving the thymus Nude (nu/nu) mice : • Hairless mouse spontaneously generated in a mouse facility • Athymic or vestigial thymus, so very few T cells. • In both mice and humans, mutations in FOXN1 (also known as WHN), transcription factor selectively expressed in skin and thymus • FOXN1 is necessary for the differentiation of thymic epithelium and the formation of a functional thymus • B cell development is normal

11. Winged helix deficiency (nude) (Table 2.9) Nasal dystrophy, alopecia of scalp, eyebrows, eyelashes

13. FOX: forkhead box The crystal structure of the forkhead domain: “winged box” owing to its double-wing structure like a butterfly

14. SCID mouse and nude mouse Nude mice no thymus, B cells+, few T cells defect in the gene for Whn, a transcription factor required for terminal epithelial cell differentiation, normal bone marrow SCID mice Defect in bone marrow, not in the thymus

15. Reciprocal grafts of thymus and bone marrow between SCID and nude mice Nude bone marrow precursors develop normal in a scid thymus Transplanting a scid thymus into nude mice leads to T-cell development SCID bone marrow cannot develop T cells, even in a wild-type recipient

16. Hyper IgE syndrome (HIES, Table 2.5) • Autosomal dominant hyper-IgE recurrent infection syndrome • Davis et al. (1966) called the disorder 'Job’s syndrome' because of phenotypic similarity to the biblical figure Job: 'Satan...smote Job with sore boils from the sole of his foot unto his crown' (Job 2:7) • Defect in STAT3, which is activated downstream of IL-6 and IL-23 • Deficient Th17 differentiation • Defective neutrophil recruitment • Bacteria and fungal infections http://www.omim.org/entry/147060?search=147060&highlight=147060

19. Epithelium Neutrophil Dendritic cell http://downloads.info4pi.org/pdfs/Inmunocytes-against-Candida---The-importance-of-our-TH17-army.pdf

20. HIES: Hyper IgE syndrome

21. Table 3. Predominantly antibody deficiency CVID

23. Immunoglobulin levels in newborn infants fall to low levels at about 6 month of age • IgG is actively transported across the placenta from the mother during gestation • After birth, IgG production does not begin for 6 months • IgG levels are low from the age of 3 months to 1 year

24. Endothelial cells of fetal capillary Villi Syncytio-trophoblast to the fetal circulation Maternal blood

25. FcRn: neonatal Fc receptor for IgG

26. Syncytiotrophoblasts are bathed in maternal blood and internalize serum containing maternal IgG. FcRn is expressed in the internal vesicles of the syncytiotrophoblast. On acidification in the endosome, FcRn binds to maternal IgG and transcytoses it to the fetal circulation where it is released at physiological pH.

27. B cell immunodeficiencies • Encapsulated bacteria (Haemophilus influenza, Pneumococcus spp., etc..) have polysaccharide capsules that are not bound by pattern recognition receptors on macrophages and neutrophils, and therefore are not phagocytosed directly • Thus, antibody and complement are critical for binding the bacteria and initiating opsonization. • Antibody is also critical for some viruses, particularly those that infect the gut (enteroviruses)

28. X-linked agammaglobulinemia (Table 3.1a) • The first description of an immunodeficiency disease was by Ogden C. Bruton (1952) in a child that failed to produce antibody • The disease was later termed: Bruton’s X-linked agammaglobulinemia (XLA) • Recurrent bacterial infection, such as Streptococcus pneumoniae, and chronic viral infections, such as hepatitis B and C, poliovirus, echovirus, coxsackie viruses and adenovirus Primary role for secretory IgA in host defense (T cells are normal) • Disease is caused by a mutation in a protein tyrosine kinase important for B cell signaling: Btk: Bruton’s tyrosine kinase • During the first 6 to 9 months, remain well by maternally transmitted IgG antibodies, thereafter, repeated infections with extracellular organisms, unless given prophylactic antibiotics or γ-globulin therapy

29. Btk function in B cell development Btk signaling from the pre-B cell receptor is required for development. CD79a, Table 3.1d CD79β, Table 3.1e Table 3.1a Table 5.5b Table 2.14

30. BTK gene is important for B-cell development • In XLA male, B cell development arrest • In females, one of the two X chromosomes in each cell is permanently inactivated. Choice of inactivation is random • In females, each cell has one active chromosome and one inactive chromosome. If the mutation is on the inactive copy, then there is no effect. • If the wild-type btk gene is on inactivated chromosome, no development. All B cells have the normal X chromosome. • In monocytes, equal mixture of normal and BTK mutant X chromosomes (BTK gene is required only for B cell development) in carrier

32. (A) Among lymphocyte-gated cells, only CD20+ B cells are Btk+ (B) Monocytes are also Btk+, while neutrophils are Btk- (all) CD20+ B cells are Btk protein+ No B cells Btk- cells Btk+ cells B cells and monocytes are Btk protein+

33. Many immunodeficiencies are X-linked • Most gene defects in PIDs are recessive • Many are caused by gene mutations on the X chromosome • All male with defective X chromosome gene show the disease, as males have only one X chromosome • Female carriers with one defective X chromosome are usually healthy (Table 5.3a) (Table 8.16) (Table 2.1a) (XSCID, Table 1.1a) (Btk-, Table 3.1a) (Table 3.3a, Table 1.3)

34. Hyper IgM syndrome (Table 3.3) • Normal B- and T-cell development, normal or high levels of serum IgM (as high as 10 mg/ml; normal levels are 1.5 mg/ml) • Limited IgM antibody responses against antigens that require T-cell help • Produce only very low levels of other classes of antibody because of problems with Ig class switching. • Patients are highly susceptible to infection with extracellular pathogens • At least six different gene mutations cause hyper IgM syndrome • Most common form: X-linked hyper IgM syndrome = CD40 ligand deficiency (Table 3.3a)

35. X-linked hyper IgM syndrome • Opportunistic infection, increased risk of malignancy • Deficiency in CD40 ligand (CD154) on activated CD4+ T cells • Class switching and formation of memory B cells both require contact with CD40L on helper T cells • B cells develop normally, but cannot become fully activated by most antigens • Treatment: bone marrow transplant, intravenous Immunoglobulin (IVIG) administration • Antigen bound by surface immunoglobulin on the B cell is internalized and returned to the cell surface as peptides bound to MHC class II • Helper T cells recognize the peptide and activate B cells via interaction between CD40L on T cells and CD40 on B cells

36. Interaction of B cells and helper T cells leads to CD40L expression on T cells and IL-4, 5, and 6 production, which drive the proliferation and differentiation of B cell into plasma cells and memory cells • The second signal required to activate antibody production against thymus-independent antigens is provided by recognition of microbial constituent or by extensive membrane IgM cross-linking

37. Formation of germinal centers requires B cell activation by helper T cells Hyper IgM syndrome Most common form: X-linked hyper IgM syndrome

39. FIGURE 46.2 The role of the CD40 ligand (CD154) in B cell class switching. The CD154 gene is mutated in X-linked hyper immunoglobulin M (IgM) syndrome. Thus, this is a T cell, not a B cell, defect. IL, interleukin. (From Allen RC, Armitage RJ, Conley ME, et al. CD40 ligand gene defects responsible for X-linked hyper IgM syndrome. Science. 1993;259:990) Fundamental Immunology 6th edition

40. Selective IgA deficiency (Table 3.4g) • The most common inherited form of immunoglobulin deficiency : 1 in 333 reported among some blood donors • Normal numbers of sIgA-expressing B cells, but decreased synthesis or release of IgA • Low serum IgA < 50 μg / ml (normal 2 to 4 mg / ml) • Normal or elevated levels of IgM and IgG • The absence of IgA predisposes to some types of infections (particularly respiratory), but many with an IgA deficiency are outwardly “normal”. • The cause of selective IgA deficiency is unknown • Some patients have mutations in TACI (one of the three types of receptors for BAFF and APRIL) (Table 3.2g)

41. Table 4. Diseases of immune dysregulation

43. Some deficiencies can lead to lymphoproliferative diseases (Table 4.1) • Familial hemophagocytic lymphohistiocytosis (FHL or FHLH) is caused by an inherited deficiency of perforin • Hemophagocytosis: ingestion of red blood cells by macrophages • Pfp-/- mice infected with some types of viruses result in a disease similar to FHL because the immune system is uncontrolled  demonstrates that perforin plays an important role in regulating the immune response • Hemophagocytic lymphohistiocytosis (HLH) =Hemophagocytic syndrome (HPS) =Macrophage activation syndrome

44. In FHL, mutations prevent NK cells and cytotoxic T cells from releasing their cytoplasmic granules, which leads to uncontrolled proliferation of lymphocytes and macrophages • These cells phagocytose blood cells and release huge amounts of proinflammatory cytokines • Cytokine burst explains the inflammation, fever and systemic illness • T cell and macrophage infiltration in liver, spleen, lymph nodes, bone marrow, and central nervous system • T cells and macrophages respond strongly to microbes to compensate for the CTL and NK cell defects?

46. Anemia • Thrombocytopenia • Hemophagocytosis in bone marrow, spleen, lymph node • Increased cytokine release: interferon-γ, TNF, IL-6, IL-10, macrophage colony-stimulating factor (M-CSF) • Treatment: control the cytokine burst by chemotherapy and immunotherapy with etoposide, corticosteroids and cyclosporine, followed by bone marrow transplantation

47. Hemophagocytic lymphohistiocytosis (HLH) Hemophagocytic syndrome (HPS)

48. Genetic hemophagocytic lymphohistiocytosis =primary hemophagocytic syndrome • Familial hemophagocytic lymphohistiocytosis (FHL) (Table 4.1.1) FHL1: unidentified gene on chromosome 9 FHL2: perforin (PRF1) mutation FHL3: Munc13-4 (UNC13D) mutation FHL4: syntaxin 11 (STX11) mutation FHL5: syntaxin binding protein (STXBP) 2 (Munc 18-2) mutation All four proteins are involved in the granule-mediated cytotoxic pathway of lymphocytes • FLH with hypopigmentation (Table 4.1.2) Chediak-Higashi syndrome 1: LYST (=CHS1) mutation Griscelli syndrome 2: RAB27A mutation LYST and RAB27A: role in vesicle trafficking in CTL Hermansky-Pudlak syndrome 2 (HPS2), AP3B1 mutation • (X-linked lymphoproliferative syndrome: SH2D1A mutation) NK cell inhibition leads to severe EB virus infection and sustained proliferation of CTL (Table 4.2a)