Immunodeficiency (1 of 2) Ali Al Khader, M.D. Faculty of Medicine Al-Balqa Applied University Email: [email protected] Primary immunodeficiency diseases Innate or adaptive
Most are detected in infancy (6 months 2 years) Rarebut some mild genetic forms exist in many individuals Defects in Innate Immunity Defects in Leukocyte Function: -adhesion -phagolysosome function -microbicidal activity -TLR signaling
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 Defects in leukocyte adhesion Leukocyte adhesion deficiency type 1 2 chainshared by the LFA-1 and Mac-1 integrins
Leukocyte adhesion deficiency type 2 sialyl-Lewis X, the fucose-containing ligand for E- and P-selectins defect in a fucosyl transferase Both will cause recurrent bacterial infections due to inadequate granulocyte function Defects in phagolysosome function Chdiak-Higashi syndrome: autosomal recessive defective fusion of phagosomes and lysosomes -neutropenia
-defective degranulation -delayed microbial killing Leukocytes contain giant granules 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 Defects in microbicidal activity Chronic granulomatous disease recurrent bacterial infections defects in the genes encoding components of phagocyte oxidase
X-linked membrane-bound component (gp91phox) AR cytoplasmic components (p47phox and p67phox) Defects in TLR signaling Defects in TLR3recurrent herpes simplex encephalitis Defects in MyD88bacterial pneumonias C2 deficiency The most common complement protein deficiency
Increased bacterial or viral infectionsalso 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!! Deficiency of components of the alternative pathway (properdin and factor D) Rare Recurrent pyogenic infections
C3 deficiency Serious and recurrent pyogenic infections Increased incidence of immune complex-mediated glomerulonephritis Defects in adaptive immunity Lymphocyte maturation Lymphocyte activation and function Deficiencies associated with systemic disorders
SCID Defects in lymphocyte maturation Affected infants: -oral candidiasis -extensive diaper rash -failure to thrive Some patients: morbilliform rashmaternal T cells attack the fetusGVHD Without HSC transplantationdeath in the first year The genetic lesion is not known in many cases
OftenT-cell problemsecondary humoral problem X-linked SCID Defects in lymphocyte maturation The most common form of SCID50% to 60% of cases Mutation: -chain (c) subunit of cytokine receptors receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, and IL-21 IL-7survival and proliferation of lymphoid progenitors, esp. T-lineage T-cell numbers are greatly reduced
IL-15maturation and proliferation of NK cellsalso deficiency of NK cells Defects in lymphocyte maturation Autosomal recessive SCID Deficiency of adenosine deaminase (ADA) accumulation of deoxyadenosine and its derivatives (e.g., deoxy-ATP) toxic to rapidly dividing immature lymphocytes Defects in lymphocyte maturation
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 chain Defects in lymphocyte maturation Clinical manifestations & treatment of SCID In the two most common forms (c mutation and ADA deficiency):
-the thymus: small and devoid of lymphoid cells -other lymphoid tissues: hypoplastic 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 Defects in lymphocyte maturation X-Linked agammaglobulinemia (Bruton
agammaglobulinemia) 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 Xq21.22associated 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 Defects in lymphocyte maturation
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 aureusneed to be opsonized by antibodies also: viruses in the bloodstream or mucosal secretions or being passed from cell to cellespecially enteroviruses, such as echovirus, poliovirus,
and coxsackievirus can disseminate to the nervous system via the blood also: persistent Giardia lamblia infections Most intracellular viral, fungal, and protozoal infections are handled quite well by the intact T cell mediated immunity Defects in lymphocyte maturation
Bruton agammaglobulinemia, contd Robbins and Cotran pathologic basis of disease 9th edition Defects in lymphocyte maturation Bruton agammaglobulinemia, contd Autoimmune arthritis and dermatomyositis35% induced by chronic infections associated with the immune
deficiency Prophylactic intravenous Ig therapy allows most individuals to reach adulthood Defects in lymphocyte maturation DiGeorge syndrome (Thymic hypoplasia) A T-cell deficiency Failure of development of the third and fourth pharyngeal pouches
-hypoplasia or lack of the thymus -tetany -congenital defects of the heart and great vessels -abnormal appearance of the mouth, ears, and facies -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 Defects in lymphocyte maturation
DiGeorge syndrome, contd In many cases, DiGeorge syndrome is not a familial disorder Deletion 22q11in more than 50% of patients TBX1 gene DiGeorge syndrome is a component of the 22q11 deletion syndrome Defects in lymphocyte activation and function Hyper-IgM syndrome
IgM antibodies are produced but deficiency in IgG, IgA, and IgE antibodies Inability of helper T cells to deliver activating signals to B cells and macrophages CD40 on B cells, macrophages and dendritic cells interact with CD40L (also called CD154) on antigen-activated T cells Ig class switching and affinity maturation in B cells microbicidal functions of macrophages Defects in lymphocyte activation and function
Hyper-IgM syndrome, contd 70%: X-linked mutations in CD40L located on Xq26 The remainder are autosomal recessive -mutations of CD40 -mutations of activation-induced cytidine deaminase (AID) required for Ig class switching and affinity maturation Defects in lymphocyte activation and function
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 opsonization by IgG Also Pneumocystis Jirovecidefective CD40L mediated macrophage activation
Occasionally: -autoimmune hemolytic anemia, thrombocytopenia, and neutropenia -proliferation of IgM-producing plasma cells that infiltrates the mucosa of the gastrointestinal tractin older patients Defects in lymphocyte activation and function Common variable immunodeficiency Relatively frequent Affects both sexes equally
Poorly defined entity Heterogeneous group of disorders The common feature is hypogammaglobulinemia of all classes but sometimes only IgG Sporadic and inherited forms In contrast to x-linked agammaglobulinemia Relatives of such patients have a high incidence of selective IgA deficiency 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 Defects in lymphocyte activation and function Common variable immunodeficiency, contd Abnormalities in B cells and helper T cell-mediated activation of B cells Reported to be abnormal here: receptor for a cytokine called BAFF also reported in these cases: abnormalities in ICOS (inducible costimulator)homologous to CD28
Defects in lymphocyte activation and function 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 Defects in lymphocyte activation and function Common variable immunodeficiency, clinical notescontd As in X-linked agammaglobulinemia20% have autoimmune diseases
including RA The risk of lymphoid malignancy is also increased Increase in gastric cancerreported Defects in lymphocyte activation and function Isolated IgA Deficiency Common Less common in blacks and Asians Extremely low levels of both serum and secretory IgA Familial or acquired
toxoplasmosis, measles, or some other viral infections Most are asymptomatic Mucosal defenses are weakened Symptomatic patients commonly present with recurrent sinopulmonary infections and diarrhea Defects in lymphocyte activation and function Isolated IgA Deficiency Some individuals: also deficient in the IgG2 and IgG4 subclasses of IgGparticularly prone to infections 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 Defects in lymphocyte activation and function Isolated IgA Deficiency The defect in IgA deficiency is impaired differentiation of naive B lymphocytes to IgA-producing plasma cells
BAFF receptor defects have been reported Defects in lymphocyte activation and function X-Linked Lymphoproliferative Syndrome Inability to eliminate Epstein-Barr virus (EBV) -Fulminant infectious mononucleosis -Increased risk of tumors In about 80% of cases:
mutation: adaptor molecule called SLAM-associated protein (SAP) for activation of NK cells and T and B lymphocytes Immunodeficiencies Associated with Systemic Diseases Wiskott-Aldrich Syndrome X-linked disease characterized by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection, resulting in early death Ataxia Telangiectasia autosomal-recessive disorder characterized by abnormal gait (ataxia), vascular malformations (telangiectases), neurologic deficits,
increased incidence of tumors, and immunodeficiency Thank You
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