Immunodeficiency. Most are detected in infancy (6 months 2 years) >> because it s genetic not acquired

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1 The sheet include slide in bold Immunodeficiency Mohammad Jomaa Primary immunodeficiency diseases The primary immunodeficiency is genetic disorder Innate or adaptive Most are detected in infancy (6 months 2 years) >> because it s genetic not acquired Rare but some mild genetic forms exist in many individuals >> although rare but some cases present as spectrum of disease (not full blown picture of the disease)>> that s mean some people have genetic heterogeneity or allelic polymorphism that make them more susceptible to infection than others Defects in Innate Immunity When we say innate immune system we mean (phagocyte and complement) Defects in Leukocyte Function: (the affected phagocyte function as mentioned bellow caused by genetic defect in the gene controlling this function (genetic =primary) ) -adhesion > adhesion of WBC to the endothelium and move the tissue -phagolysosome function -microbicidal activity > like reactive oxygen species -TLR signaling > pattern recognition receptor Deficiencies Affecting the Complement System: -C2 -components of the alternative pathway (properdin and factor D) -C3 -terminal components of complement C5, 6, 7, 8, and 9 (complement of the membrane attack complex) #Slide 4 Defects in leukocyte adhesion >the result disease of adhesion defect as follow: Leukocyte adhesion deficiency type 1 The affected part is the β2 chain(low) the β2 chain shared by (part of) the LFA-1 and Mac-1 integrins

2 As we remember the integrins which is protein (as receptor) found on surface of WBC and have role in firm adhesion between the WBC and the endothelium (by ligand on its surface such as: ICAM & VCAM) for moving out of blood vessel to the tissue Leukocyte adhesion deficiency type 2 sialyl-lewis X(low), the fucose-containing ligand for E- and P-selectins The defect affect the enzyme fucosyl transferase that fuse the fucosyl with protein to form sialyl-lewis x residues on the WBC **there is a glycoprotein on the surface of the WBC called sialylated (sialyl-lewis(sugar) fused with protein on the surface of the WBC) this glycoprotein bind to the E and P selectins which found on the surface of the endothelium >> this function is important in the rolling defect in a fucosyl transferase **As the defect or disease we mentioned above affect granulocyte in the inflammation (mainly inflammation against bacteria)>> that result in increased susceptibility to bacterial infection Both will cause recurrent bacterial infections due to inadequate granulocyte function #slide 5 Defects in phagolysosome function Chédiak-Higashi syndrome: >> defect in lysosomal trafficking that result in defect in phagolysosome synthesis autosomal recessive defective fusion of phagosomes and lysosomes This syndrome result in this 3 manifestation -neutropenia -defective degranulation -delayed microbial killing Leukocytes contain giant granules >>apparent phagolysosome (but actually its defected) Abnormalities in melanocytes (leading to albinism), cells of the nervous system (associated with nerve defects), and platelets (causing bleeding disorders) The gene encodes a large cytosolic protein called LYST, which is believed to regulate lysosomal trafficking

3 Defects in microbicidal activity (mainly reactive oxygen specious >>mainly affect the phagocyte oxidase (or called NADPH oxidase) enzyme which considered as first enzyme for synthesis of the reactive oxygen specious (particularly super-oxide O2- )) Chronic granulomatous disease recurrent bacterial infections defects in the genes encoding components of phagocyte oxidase The defect may affect two component or gene: X-linked >> membrane-bound component (gp91phox) AR >> cytoplasmic components (p47phox and p67phox) phox: phagocyte oxidase #slide 7 Defects in TLR signaling >> the defect may affect the TLR itself or in molecule in the signaling pathway of the TLR Defects in TLR3 recurrent herpes simplex encephalitis **TLR3(as PRR) bind to the viral RNA(as PAMP) #slide 8 Defects in MyD88 bacterial pneumonias >> defect in the signaling C2 deficiency >> its important in forming antigen-antibody complex and activation of the classical pathway of complement The most common complement protein deficiency Increased bacterial or viral infections also if C4 is deficient Many patients have no clinical manifestations In some of these patients, as well as in patients with C1q deficiency, the dominant manifestation is SLE-like autoimmune disease!! >> because C2 and C1q(also C3 and C4) is important in washing the antigen-antibody complex by complement receptor on the surface of the complex>> finally result in accumulation of the complex and the manifestation appear as SLE-like autoimmune disease. Deficiency of components of the alternative pathway (properdin and factor D) ** properdin and factor D> its activator for complement

4 Rare Recurrent pyogenic infections >> mainly caused by bacterial endotoxin (gram negative bacteria) and may cause by gram positive C3 deficiency Slide 11 Serious and recurrent pyogenic infections Increased incidence of immune complex-mediated glomerulonephritis Defects in adaptive immunity The defect in the adaptive immune system may affect : Lymphocyte maturation Lymphocyte activation and function Deficiencies associated with systemic disorders We will begin with Defects in lymphocyte maturation SCID: Severe combined immunodeficiency syndrome (Defects in lymphocyte maturation) Affected infants: first months of life Come with severe infection like -oral candidiasis -extensive diaper rash -failure to thrive **these patients require hematopoietic stem cell transplantation Some patients: morbilliform rash maternal T cells attack the fetus GVHD GVHD: Graft-versus-host disease >> the changes or reaction that result from allogeneic transplant, bone marrow transplant or as following case **normally when T cell from pregnant women move through the placenta to the fetus the T cells of the fetus remove it rapidly but in case of the SCID the fetus don t have T cell required to remove the maternal T cell >>result in increase of the maternal T cell which attack fetus tissue and cause rash called morbilliform rash (like measles appearance) the case called maternal engraftment Without HSC transplantation death in the first year The genetic lesion is not known in many cases

5 Often T-cell problem secondary humoral problem (B cell problem due to the >>T cell dependent B cell activation and response) X-linked SCID The most common form of SCID 50% to 60% of cases Mutation: γ-chain (γc) subunit of cytokine receptors receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, and IL-21 most imprtant IL-7 survival and proliferation of lymphoid progenitors, esp. T-lineage >>no T cells development T-cell numbers are greatly reduced (because there is no proliferation, maturation and development of the T cells) IL-15 maturation and proliferation of NK cells also deficiency of NK cells Autosomal recessive SCID Deficiency of adenosine deaminase (ADA) deficiency in this enzyme result in : accumulation of deoxyadenosine and its derivatives (e.g., deoxy-atp) result in >> slide 15 toxic to rapidly dividing immature lymphocytes Several other less common causes of autosomal recessive SCID have been identified: RAG mutations blocks the development of T and B cells. Jak3 (an intracellular kinase) signal transduction through the common cytokine receptor γ chain Clinical manifestations & treatment of SCID In the two most common forms (γc mutation (x-linked) and ADA deficiency (autosomal recessive)): -the thymus: small and devoid of lymphoid cells -other lymphoid tissues: hypoplastic

6 marked depletion of T-cell areas in some cases both T-cell and B-cell zones X-linked SCID is the first human disease in which gene therapy has been successful 20% of these patients have developed T-cell lymphoblastic leukemia ** T-cell lymphoblastic leukemia may result from 1) The gene used in the gene therapy amplified by viruses (viral factor) and some viruses have an oncogene which finally result in tumor such as leukemia in the recipient 2) The over activation of the transcription factor or over expression of transplanted gene which is uncontrolled by the body and result finally in leukemia Slide 17 X-Linked agammaglobulinemia (Bruton agammaglobulinemia) (Defects in lymphocyte maturation) Failure of B-cell precursors (pro-b cells and pre-b cells) to develop into mature B cells Mutation: Bruton tyrosine kinase (Btk) the gene is on the long arm of the X chromosome at Xq21.22 associated with Ig receptor complex Because light chains are not produced, the complete antigen receptor molecule (which contains Ig heavy and light chains) cannot be assembled and transported to the cell membrane ** Bruton tyrosine kinase it s a signal transduction of the pre-b cell receptor, this tyrosine kinase is responsible for induction to remove of surrogate light chain and synthesis the original light chain and finally formation of the immunoglobulin **in case of deficiency of Bruton tyrosine kinase this result in immature B cells Bruton agammaglobulinemia, clinical notes Not apparent until 6 months of age Recurrent bacterial infections of the respiratory tract pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia Almost always: the infections are by Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus need to be opsonized by antibodies **one of the most important function of IgG is to opsonization. so in case of Btk deficiency >>result in recurrent bacterial infection which opsonized and killed by Ig (like IgG) Most intracellular viral, fungal, and protozoal infections are handled quite well by the intact T cell mediated immunity

7 also: viruses in the bloodstream or mucosal secretions or being passed from cell to cell especially enteroviruses, such as echovirus, poliovirus, and coxsackievirus can disseminate to the nervous system via the blood **viruses are very danger if reach brain (CNS) such as echovirus (cause echovirus encephalitis) also: persistent Giardia lamblia infections >> because there is no secretory IgA Slide 20 Autoimmune arthritis and dermatomyositis 35% induced by chronic infections associated with the immune deficiency **in case of Btk deficiency (immune deficiency) result in chronic infection which result in autoimmune disease in genetically susceptible patient Slide 21 Prophylactic intravenous Ig therapy allows most individuals to reach adulthood DiGeorge syndrome (Thymic hypoplasia) (Defects in lymphocyte maturation) A T-cell deficiency

8 Caused by Failure of development of the third and fourth pharyngeal pouches The manifestation of the DiGeorge syndrome as follow: -hypoplasia or lack of the thymus -tetany >> because there is no calcium result of no parathyroid gland -congenital defects of the heart and great vessels -abnormal appearance of the mouth, ears, and facies (elephants face) -low numbers of T lymphocytes in the blood and lymphoid tissues -poor defense against certain fungal and viral infections -Ig levels may be normal or reduced, depending on the severity of the T-cell deficiency In many cases, DiGeorge syndrome is not a familial disorder Deletion 22q11 in more than 50% of patients TBX1 gene **mutation in the TBX1 gene in the chromosome 22 DiGeorge syndrome is a component of the 22q11 deletion syndrome ** the 22q11 deletion syndrome have many congenital anomalies one of them is DiGeorge syndrome Now we will talk about Defects in lymphocyte activation and function Hyper-IgM syndrome (Defects in lymphocyte activation and function) IgM antibodies are produced but deficiency in IgG, IgA, and IgE antibodies Inability of helper T cells to deliver activating signals to B (activation mean isotype switching) cells and macrophages CD40 on B cells, macrophages and dendritic cells interact with CD40L (also called CD154) on antigen-activated T cells lead to (normally).. 1- Ig class switching and affinity maturation in B cells 2- increase microbicidal functions of macrophages

9 **there is two form of the Hyper IgM syndrome (x-linked & autosomal recessive) a- 70%: X-linked (X-linked affect mainly male) mutations in CD40L located on Xq26 b- The remainder are autosomal recessive -mutations of CD40 -mutations of activation-induced cytidine deaminase (AID) this enzyme required for Ig class switching and affinity maturation Slide 25 Hyper-IgM syndrome, clinical notes Normal or elevated levels of IgM No IgA or IgE Extremely low levels of IgG The number of B and T cells is normal Recurrent pyogenic infections decrease opsonization by IgG Also Pneumocystis Jiroveci defective CD40L mediated macrophage activation Occasionally: -autoimmune hemolytic anemia, thrombocytopenia, and neutropenia -proliferation of IgM-producing plasma cells that infiltrates the mucosa of the gastrointestinal tract in older patients >> proliferation of the plasma cell and attack the GIT in picture like multiple myeloma Common variable immunodeficiency (Defects in lymphocyte activation and function) Relatively frequent Affects both sexes equally (in contrast to x-linked agammaglobulinemia which affect male mainly) Poorly defined entity Heterogeneous group of disorders

10 The common feature is hypogammaglobulinemia of all classes but sometimes only IgG Sporadic and inherited forms Relatives of such patients have a high incidence of selective IgA deficiency In contrast to x-linked agammaglobulinemia Slide 27 Normal or near-normal numbers of B cells in the blood and lymphoid tissues. These B cells, however, are not able to differentiate into plasma cells Abnormalities in B cells and helper T cell-mediated activation of B cells Reported to be abnormal here: receptor for a cytokine called BAFF **BAFF it member of the tumor necrosis factor family (TNF) >> its important in B cell development and maturation also reported in these cases: abnormalities in ICOS (inducible costimulator) homologous to CD28 (this ICOS (CD28) have important role in the activation of T cell) Common variable immunodeficiency, clinical notes Resembles X-linked agammaglobulinemia recurrent sinopulmonary pyogenic infections 20%: recurrent herpesvirus infections Serious enterovirus infections causing meningoencephalitis may also occur prone to the development of persistent diarrhea caused by G.lamblia the onset of symptoms is later than X-liked agammaglobulinemia Lymphoid follicles in nodes, spleen, and gut are hyperplastic due to incomplete B cell activation >> that result in accumulation of the immature B cell and finally hyperplastic Slide 30 As in X-linked agammaglobulinemia 20% have autoimmune diseases including RA The risk of lymphoid malignancy is also increased >> maybe due to uncontrolled proliferation of the B cells Increase in gastric cancer reported Isolated IgA Deficiency (Defects in lymphocyte activation and function)

11 **IgA deficiency may found in celiac disease (although low IgA)>> this correlation may exit due to higher incidence of the isolated IgA deficiency in contrast to other immunodeficiency disease (common). From internet: An estimated 2% of people with celiac disease also have selective immunoglobulin A (IgA) deficiency. If someone has IgA deficiency and celiac disease, the IgA deficiency can cause a false negative on a celiac disease antibody test. Common relatively to other immunodeficiency Less common in blacks and Asians (more in white) Extremely low levels of both serum and secretory IgA Familial or acquired Most are asymptomatic toxoplasmosis, measles, or some other viral infections Slide 31 Slide 33 Mucosal defenses are weakened If Symptomatic patients commonly present with recurrent sinopulmonary infections and diarrhea (GI infection due to defected secretory IgA which responsible for GI mucosal defense ) Some individuals: also deficient in the IgG2 and IgG4 subclasses of IgG particularly prone to infections (due to the opsonization function of the IgG) High frequency of respiratory tract allergy and a variety of autoimmune diseases, particularly SLE and rheumatoid arthritis When transfused with blood containing normal IgA, some of these patients develop severe, even fatal, anaphylactic reactions, because the IgA behaves like a foreign antigen The defect in IgA deficiency is impaired differentiation of naive B lymphocytes to IgAproducing plasma cells BAFF receptor defects have been reported X-Linked Lymphoproliferative Syndrome (Defects in lymphocyte activation and function) Inability to eliminate Epstein-Barr virus (EBV) (mean the patient are more susceptible to have infection by (EBV) **EBV= HHV4 (human herpes virus 4) Which result in.. 1- Fulminant infectious mononucleosis (also called kissing disease) which result from EBV infection 2- Increased risk of tumors >>because EBV is an oncogenic virus (especially nasopharyngeal carcinoma, many type of the B cell lymphoma and some type of the hodgkin's lymphoma )

12 In about 80% of cases: mutation: adaptor molecule called SLAM-associated protein (SAP) have function for activation of NK cells and T and B lymphocytes (NK & T cells have role in killing viruses..so if there is no NK & T cells >>more susceptible for viral infection) Slide 34 Immunodeficiencies Associated with Systemic Diseases **these diseases are a syndrome with one of its manifestation being immunedeficiency Wiskott-Aldrich Syndrome X-linked disease (recessive) characterized by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection, resulting in early death **defect in Wiskott-Aldrich Syndrome protein, which bind to the cytoskeleton **these patients require bone marrow transplantation Ataxia Telangiectasia autosomal-recessive disorder characterized by abnormal gait (ataxia), vascular malformations (telangiectases), neurologic deficits, increased incidence of tumors, and immunodeficiency ** The defect affects the gene responsible for DNA repair gene (atm gene) which responsible for stops cell division and begin repair (such as PT53 gene) >>in case the repair don t occur and the cells continue to divide>> will finally result in tumor formation **ataxia mean problem in gait which mean problem in patient walking Good luck ^^