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Immunodeficiency Diseases PowerPoint Presentation

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Description : Check out this medical presentation on Ataxia-Telangiectasia, which is titled "Immunodeficiency Diseases", to know about immunodeficiency diseases.

Tags : Ataxia-Telangiectasia, Immunodeficiency, classification, B cell deficiency, T Cell deficiency, SCID, drug induced

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IMMUNODEFICIENCY DISEASES By: Dr. Puneet Kumar Gupta Assistant Professor, Microbiology,
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Introduction Immunodeficiency diseases Defence mechanisms of body are impaired→ repeated microbial infections specific immune functions- humoral / cell- mediated immunity / both Non-specific mechanisms such as phagocytosis & complement.
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Introduction Primary or Secondary 10 : abnormalities in development of immune mechanisms 20 : Consequences of disease, drugs, nutritional inadequacies & other processes interfere with proper functioning of mature immune system
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Primary immunodeficiency diseases Inducement: heredity,developmental defect Age: infancy and childhood Pathogenesis: differentiation & development of hemopoietic stem cells 1. IDD characterized by humoral immunity deficiency 2. IDD characterized by cellular immunity deficiency 3. Combined immunodeficiency diseases 4. Nonspecific immunodeficiency diseases
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Phagocyte function
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Common features of primary immunodeficiency diseases Most of these diseases are inherited recessive disorders many are X-linked (M>F) Recurrent or over-whelming infections in early childhood Abnormality of acquired immunity Innate immunity deficiencies are rare.
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Common features of primary immunodeficiency diseases Diseases resulting from developmental abnormality at initial stage of haemopoietic development, have more severe immunodeficiency usually of both innate & acquired immunity Defects occurring at later stages usually lead to more specific deficiency of cellular or humoral variety
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Humoral immunodeficiencies ( B cell defect ) X-linked agammaglobulinemia Transient hypogammaglobulinemia of infancy Common variable immunodeficiency Selective immunoglobulin deficiencies Immunodeficiencies with hyper-IgM Transcobalamin II deficiency
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Cellular immunodeficiencies ( T cell defect ) Thymic Hypoplasia ( DiGeorge syndrome ) Chronic mucocutaneous candidiasis Purine nucleoside phosphorylase ( PNP ) deficiency Biotin dependent multiple cocarboxylase deficiency N K cell deficiency Idiopathic CD 4 lymphopenia
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III. Combined immunodeficiencies ( B & T cell defects): Cellular immunodeficiency with abnormal immunoglobulin synthesis ( Nezelof syndrome ) b.Ataxia telangiectasia c. Wiskott-Aldrich syndrome d.Immunodeficiency with thymoma ( Good’s syndrome ) e. Immunodeficiency with short-limbed dwarfism / cartilage hair hypoplasia f. Episodic lymphopenia with lymphocytotoxin g.Severe combined immunodeficiencies h. Omenn syndrome i. Bare lymphocyte syndrome j. Duncan’s syndrome k. Reticular dysgenesis l. Nijmegen breakage syndrome m. GVHD
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B. Disorders of non-specific immunity : Disorders of phagocytosis: 2.Disorders of complement : Chronic granulomatous disease a. Complement component deficiencies Myeloperoxidase deficiency b. Complement inhibitor deficiencies Chediak-Higashi syndrome Leucocyte G6PD defeciency Job’s syndrome Tuftsin deficiency Lazy leucocyte syndrome Hyper-IgE syndrome Actin binding protein deficiency Shwachman’s disease
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I. IDD characterized by humoral immunity deficiency B cell defects ( 50-60% ) It causes deficiency of Ig and antibody Features： increased susceptibility to bacteria, enterovirus, intestine parasites，delayed in growth and development increased incidence of autoimmune diseases, malignant tumor reduced numbers of peripheral blood B cells，absent or reduced levels of Ig. Pathogenesis: Block of differentiation & development of B cells, reduced function of Th cells
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X-LINKED AGAMMAGLOBULINEMIA Described by Bruton ( 1952 ) 1st immunodeficiency disease recognised. Genetic features: x-linked recessive inheritance, males. Pathogenesis: block in differentiation & development of the pre-B cells. Incidence : 1: 100,000 (UK) Recurrent serious infections with pyogenic bacteria, pneumococci, streptococci, meningococci, Pseudomonas & H influenzae. Live microbial vaccines should not be given to children. Immunological features: Results in an absence or severe reduction in B lymphocytes & Ig of all types.
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The Btk gene Located on the X chromosome. Gene consists of 19 exons over a length of DNA of 37 kilobases. Function of the Btk gene product is related to BCR signalling. Without Btk pre-B cells fail to develop into mature B cells.
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Clinical Findings LITTLE BOYS WITH BIG INFECTIONS! Symptoms appear at 6-9 months of age (after loss of maternal Ig) . Sites of infection: mucous membranes, ear (otitis media), lungs (bronchitis/pneumonia), blood (sepsis), gut (Giardia, or enterovirus), skin, eyes, meningitis. Also seen: joint problems, kidney problems, neutropenia, malignancy in older patients.
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Tonsils & adenoids are atrophic. LN biopsy : depletion of bursa dependent areas Plasma cells & germinal centres absent even after antigenic stimulation—No Ab formation Marked ↓ in proportion of B cells in circulation. CMI not affected Delayed hypersensitivity of tuberculin & contact dermatitis types Allograft rejection is normal Arthritis, hemolytic anaemia & atopic manifestations No Wheal & flare response of atopic hypersensitivity
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Little boys with big infections 6 to 9 months old
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Pneumococus streptococus Hemophilus Patients with XLA repeatedly acquire infections with extracellular pyogenic organisms such as:
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Otitis Media Pneumonia Sinusitis
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TREATMENT Intravenous Immunoglobulin (IVIG):300mg/kg of bd wt in 3 doses followed by monthly inj of 100mg/kg. Whole plasma infusion Donors being tested for hepatitis & other transmissible infections.
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Selective immunoglobulin deficiencies 1% of all patients with recurrent infection. Isolated IgA deficiency: MC in this group incidence 0.2% in normal populations. Immunological features: Serum IgA<5mg/dl but normal IgM and IgG Genetic features : IgA Deficiency and genetic factors: association with HLA-A2, B8 and DW3 or A1 and B8.
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Pathogenesis: failure in terminal differentiation of B cells due to intrinsic B cell defect or abnormal T cell help (TGF-B,IL-5) or in B cell responses to these cytokines C/F: atopic disorders Recurrent infections in respiratory tract, alimentary canal, urogenital tract. .
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Immunodeficiency with hyper IgM Immunological features： increased level of IgM ( 10 mg/ml )， decreased levels of other Ig Pathogenesis: absent of the T cell effector CD40L，CD40L ( CD154 ) can not bind to CD40 of B cells→do not stimulate B cells to undergo Ab class switching Genetic features：X-linked recessive inheritance，boy Clinical features：recurrent pyogenic infections & autoimmune processes such as thrombocytopenia , neutropenia, hemolytic anaemia & renal lesions. Sometimes seen in congenital rubella.
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IgG↓ IgE↓ IgA↓ IgM ↑↑ Serum levels of immunoglobulin in Hyper IgM syndrome
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Hyper IgM syndrome Defect in CD40 ligand T cell B cell CD40 ligand CD40 Ig Class switch
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TRANSIENT HYPOGAMMAGLOBULINEMIA Abnormal delay in initiation of IgG synthesis in some infants. Maternal IgG is slowly catabolised in newborn & reaches 200mg/100ml by 2nd month. Delay in synthesis of its own IgG by this age, immunodeficiency occurs. Infants of both sexes. Recurrent otitis media & respiratory infections Spontaneous recovery: 18 -30 months of age. Some cases require treatment with gammaglobulin.
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COMMON VARIABLE IMMUNODEFICIENCY Late onset hypogammaglobulinemia: manifests by 15-35 years of age Immunological features : total Ig<300 mg/100ml IgG< 250 mg/100ml B cells present in normal numbers, but defective in their ability to differentiate into plasma cells & secrete Ig Increased suppressor T cell & diminished helper T cell activity Clinical features :recurrent pyogenic infections & increased autoimmune diseases. Malabsorption & Giardiasis are common. Treatment : administration of gammaglobulin preparations I.M or I.V.
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CVID has an almost equal sex distribution
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Normal lymphoid follicle Normal number of circulating B cell Hypogammaglobulinemia CVID
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Transcobalamin II deficiency Genetic features : autosomal recessive Immunological features : depleted plasma cells, diminished immunoglobulin levels & impaired phagocytosis. Clinical features : patients show metabolic effects of vitamin B12 deficiency including Megaloblastic anaemia & intestinal villous atrophy. Treatment :Vitamin B12 – restore hematopoietic , gastrointestional & B cell functions, but not phagocytic activity.
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32 B-Cell Deficiency Disorders
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II. IDD characterized by cellular immunity deficiency T cell defects ( 5-10% ). also Ig deficiencies because B and T cell immune systems are interdependent and cytotoxic disorders as well. Features increased susceptibility to intracellular microbes Delay in growth and development death in the early age increased incidence of malignant tumor reduced numbers of peripheral blood B cells，no reaction to DTH ，no reaction to HVG block in the differentiation and development of the T cells
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DiGeorge/Arch Syndrome Developmental defect 3rd & 4th pharyngeal pouches Aplasia or hypoplasia of thymus & parathyroid glands. Probably due to some intrauterine infection or other complications. gene deletions in DiGeorge chromosomal region at 22q11 & mutations in other unknown genes M=F DiGeorge syndrome may be partial (some T-cell function exists) or complete (T-cell function is absent).
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Facial Defects: Infants low-set ears, fish shaped mouth, midline facial clefts, a small receding mandible ( micrognathia) , hypertelorism, a shortened philtrum, notched ear pinnae, antimongoloid slant congenital heart disorder Thymic and parathyroid hypoplasia or aplasia, causing T-cell deficiency and hypoparathyroidism. Recurrent infections begin soon after birth, but the degree of immunodeficiency varies considerably, and T-cell function may improve spontaneously. Hypocalcemic tetany appears within 24 to 48 h of birth.
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usually associated with Fallot’s tetrology . Frequent presenting sign occurs within first 24 hrs of life. Patients who survive the neonatal period show enhanced susceptibility to viral, fungal & bacterial infections, which ultimately prove fatal. Thymus-dependent areas of LN & spleen are depleted of lymphocytes. Circulating T cells are reduced in number. Immunological features : Primarily involves CMI humoral immune mechanismis largely unaffected. Delayed hypersensitivity & graft rejection are depressed. Antibody response to primary antigenic stimuli is normal but secondary response to many antigens is impaired.
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Chronic mucocutaneous candidiasis : Abnormal immunological response to Candida albicans C/F: Severe chronic candidiasis of mucosa, skin & nails. Don’t show increased susceptibility to other infections but often have endocrinopathies CMI to candida is deficient. Delayed hypersensitivity to candida antigens is absent but circulating Ab to them are found in high titres. Intracellular killing of candida is defective. Treatment : Transfer factor therapy along with amphotericin B.
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Purine nucleoside phosphorylase ( PNP) deficiency Enz PNP is involved in the sequential degradation of purines to hypoxanthine & finally uric acid Genetic features : autosomal recessive inheritance. Immunological features : decreased CMI . C/F: Recurrent or chronic infection usually present with hypoplastic anaemia & recurrent pneumonia, diarrhea & candidiasis Diagnosis : A low serum uric acid
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3、 Combined immunodeficiency diseases ( 20% ) : 1）SCID: severe combined immunodeficiency disease 2） immunodeficiency diseases with enzymes defect 3） immunodeficiency diseases with other severe defects
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Severe combined immunodeficiencies (SCID) Combined deficiency of humoral & cellular immunity . Usually autosomal recessive disorder, X-linked form (M>F) called primary lymphopenic immunologic deficiency IL-2Rγ-chain defect is MC that leads to defective signalling by the IL-2, IL-4, IL-7, IL-9 & IL-15. Variety of SCID characterised by CD 8+ T cells deficiency. It involves a tyrosine kinase- ZAP-70.Consequently the T cell signalling is defective.
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Severe combined immunodeficiencies (SCID) Deficiency of recombinases RAG-1 & 2 – as they required for gene rearrangement, both T & B cells are affected. Immunological features : decreased number of lymphocytes, thymus is either not developed or very poorly developed, small number of T cells fail to respond to antigens & experimental mitogens.
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KNOWN CAUSES OF SCID
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Common Features of Severe Combined Immunodeficiency (SCID) Failure to thrive Onset of infections in the neonatal period Opportunistic infections Chronic or recurrent thrush Chronic rashes Chronic or recurrent diarrhea Paucity of lymphoid tissue Immunity is so low that even the live attenuated vaccines are not tolerated- they can produce diseases. However patient’s life can be prolonged by confinement into a sterile environment. Treatment : gene therapy.
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Wiscott-aldrich syndrome X-linked immunodeficiency which increases with age. Genetic features :defective CD43 protein gene on short arm of X chromosome ( Xp11 ). This gene encodes a glycoprotein called sialophorin (expressed on lymphoid cell, neutrophils, macrophages & platelets) Immunological features : CMI undergoes progressive deterioration associated with cellular depletion of thymus & paracortical areas of lymphnodes.
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Serum IgM level is low IgG & IgA levels are normal or elevated humoral defect appears to be specific inability to respond to polysaccharide antigens. C/F: eczema, thrombocytopenic purpura & recurrent infections. Affected boys rarely survive the first decade of life, death being due to infection, hemorrhage or lymphoreticular malignancy. Treatment : BMT & transfer factor therapy.
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ATAXIA-TELANGIECTASIA Hereditary condition transmitted in the autosomal recessive mode, where combined immunodeficiency is associated with cerebellar ataxia, telangiectasia, ovarian dysgenesis & chromosomal abnormalities. Genetic features : Gene responsible on chromosome 11 Gene product may play a role in DNA repair ATM gene encodes Atm protein kinase, a member of phosphatidyl inositol 3-kinase family Clinical features : earliest signs- ataxia & chorioathetoid movements noticed in infancy. Telangiectasia involving the conjuctiva & face appears at 5 or 6 years of age.
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Disease is progressive, with both neurological defects & immunodeficiency becoming severe with time. Death occurs due to sinopulmonary infection early in life , or malignancy in 2nd or 3rd decade. Immunological features : ID may affect T&B cells IgA, IgE and IgG2 deficiency. T cell function is variably depressed. CMI is also defective resulting in impairment of delayed hypersensitivity & graft rejection. Treatment : Transfer factor therapy & fetal thymus transplants.
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Cellular immunodeficiency with abnormal immunoglobulin synthesis ( Nezelof syndrome ) : Group of disorders, probably of varied origin depressed CMI is associated with selectively elevated, decreased or normal levels of immunoglobulin Clinical features : recurrent fungal, bacterial, viral & protozoal diseases associated with hemolytic anaemia commonly.
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Cellular immunodeficiency with abnormal immunoglobulin synthesis ( Nezelof syndrome ) : Immunological features : marked deficiency of T cell immunity & varying degrees of deficiency of B cell immunity . Thymic dysplasia occurs with lymphoid depletion. Abundant plasma cells (spleen, LN, intestines & elsewhere in body) Inspite of normal levels of immunoglobulins, antigenic stimuli don’t induce antibody formation. Treatment : BMT, transfer factor & thymus transplantation.
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Phagocytic cell defects (10 to 15%) The ability of phagocytic cells (eg, monocytes, macrophages, granulocytes such as neutrophils and eosinophils) to kill pathogens is impaired. Cutaneous staphylococcal and gram-negative infections are characteristic. The most common phagocytic cell defects are chronic granulomatous disease, leukocyte adhesion deficiency, and Chédiak-Higashi syndrome
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Chronic granulomatous disease Defect in generation of oxidative radicals needed by the host phagocytic cells to kill the bacteria & other pathogens. Genetic features : Mutation in NADPH .X-linked congenital defect -70%, autosomal recessive form – 30%.Decreased hydrogen peroxide production due defective NADPH oxidase. Immunological features : Besides free radical generation deficiency, there are also defects in mononuclear cells to function as APCs. Both antigen processing & presentation are affected leading to inadequate T cell activation. Humoral & cellular immune response are normal.
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Clinical features : recurrent infection with low grade pathogens, starting early in life progress & outcome fatal Chronic suppurative granulomatous lesions develop in skin & lymph nodes, along with hepatosplenomegaly, progressive infiltration of lungs & granulomatous septic osteomyelitis. Diagnosis : NBT ( Nitroblue tetrazolium )test : leucocytes from patients fail to reduce nitoblue tetrazolium during phagocytosis. Treatment : Interferon gamma .
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Chest X-ray in cgd
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CGD patient with skin infections due to Serratia marcescens
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Secondary immunodeficiency disorders category Endocrine GI Hematologic Iatrogenic Infectious Examples Diabetes mellitus Hepatic insufficiency, hepatitis, intestinal lymphangiectasia, protein-losing enteropathy Aplatic anemia, cancer, graft-vs-host disease, sickle cell disease Certain drugs: chemotherapeutic drugs, immunosuppressants, corticosteroids, radiation therapy; splenectomy Cytomegalovirus, Epstein-Barr virus, HIV, measles virus, varicella-zoster virus
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Continued…. Nutritional Physiologic Renal Rheumatologic Other Alcoholism, undernutrition Physiologic immunodeficiency in infants due to immaturity of immune system, pregnancy Nephrotic syndrome, renal insufficiency, uremia RA, SLE Burns, chromosomal abnormalities (eg, Down syndrome), congenital asplenia, critical and chronic illness, histiocytosis, sarcoidosis
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REFERENCES Textbook of Microbiology – Ananthanaryanan & Paniker’s Roitt’s Immunology Kuby immunology
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Thank you