immunodeficiencyppt-170409084hhh703.pptx

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1. IMMUNODEFICIENCY DISEASES Presented by Dr R. Saritha Rani Moderator Dr.Shri Lakshmi

2. What is immunodeficiency? Immunodeficiency disorders are either congenital or acquired. A congenital, or primary, disorder is one you were born with. An acquired, or secondary, disorder is one you get later in life. Acquired disorders are more common than congenital disorders. Your immune system includes the following organs: Spleen Tonsils Bone marrow Lymph nodes

3. These organs process and release lymphocytes . These are white blood cells classified as B cells and T cells. B and T cells fight invaders called antigens. B cells release antibodies specific to the disease your body detects. Certain T cells destroy foreign or atypical cells.   Examples of antigens that your B and T cells might need to fight off include: Bacteria Virus Cancer cells Parasites An immunodeficiency disorder disrupts your body’s ability to defend itself against these antigens.

4. If you have a weaker immune system, you’re immunocompromised . This means your body can’t fight off infections or viruses as well as people who are not immunocompromised. While a weaker immune system is typically caused by certain diseases, malnutrition, and certain genetic disorders, it can also temporarily be caused by medications such as anticancer drugs and radiation therapy. Your immune system can also be temporarily weakened by a stem cell or organ transplant.

5. Signs of an immunodeficiency disorder Pink eye Sinus infections Thrush Cold Chronic gum disease (gingivitis) Pneumonia Yeast infections

6. TYPES OF PRIMARY IMMUNODEFICIENCY

7. Common variable immunodeficiency In which number of B cells is usually normal, but the cells do not mature and thus cannot produce immunoglobulin. In some people with this disorder, T cells (lymphocytes) also malfunction. It is usually diagnosed between the ages of 20 and 40 . The genetic mutations that cause this disorder can be inherited, but more often, they occur spontaneously.

8. Symptoms Recurring sinus and lung infections, particularly pneumonia, are common. People may develop a chronic cough, cough up blood, or have difficulty breathing. Diarrhea may occur. The spleen may enlarge. Up to 25% of people develop autoimmune disorders. Mostly people have a normal life span

9. SELECTIVE IMMUNOGLOBULIN DEFICIENCY It results in a low level of one type of antibody but levels of other IG’s are normal. most commonly affected class is IgA deficiency is usually inherited. SELECTIVE IGA DEFICIENCY Is a low level of immunoglobulin A (IgA)caused by a mutation in a specific gene or by a drug[phenytoin or sulfasalazine] . Familial history will increases the risk by about 50 times Symptoms Mostly no symptoms are observed, but some have chronic lung infections, sinusitis, and other disorders, Susceptible to pyogenic infection.

10. In X-linked SCID, the thymus contains lobules of undifferentiated epithelial cells resembling fetal thymus. whereas in SCID caused by ADA deficiency, remnants of Hassall’s corpuscles can be found. Currently, HSC transplantation is the mainstay of treatment, but X-linked SCID is the first human disease in which gene therapy has been successful.

11. Transient hypogammaglobulinemia of infancy At birth, the immune system is not fully developed. Most of the IG are transferred via the placenta from mother. In normal infants IG synthesis begins at 3 months. production of normal amounts of immunoglobulins in infants is delayed in this disease. Mainly delay in IgG synthesis . As a result, immunoglobulin levels become low starting at age 3 to 6 months and return to normal at about age 12 to 36 months. It rarely leads to serious infections, sinus, lung, or digestive tract infections, candidiasis (a fungal infection), and meningitis.

12. This condition is more common among premature infants because they receive fewer immunoglobulins from the mother. Blood tests are done to measure levels of immunoglobulins. This disorder may last for months to a few years but usually resolves without treatment.

13. X-linked agammaglobulinemia X-linked agammaglobulinemia is characterized by the failure of B-cell precursors (pro–B cells and pre–B cells) to develop into mature B cells. During normal B-cell maturation in the bone marrow, the Ig heavy-chain genes are rearranged first, in pre–B cells. These form a complex with a “surrogate” light chain on the cell surface called the pre–B cell receptor (pre-BCR) that delivers signals that induce rearrangement of the Ig light-chain genes and further maturation.

14. X-linked agammaglobulinemia is caused by mutations in a cytoplasmic tyrosine kinase, called Bruton tyrosine kinase (BTK); the gene that encodes it is located on the long arm Of the X chromosome at Xq21.22. When BTK is mutated, the pre-BCR cannot deliver the signals that are needed for light chain rearrangement, and maturation is arrested. BTK is also an important transducer of BCR signals that stimulate growth and increase cell survival in benign and malignant mature B cells, and inhibitors of BTK are effective therapies for several B cell malignancies.

15. As an X-linked disease, this disorder is seen almost exclusively in males. The disease usually does not become apparent until about 6 months of age, as maternal immunoglobulins are depleted . In most cases, recurrent bacterial infections of the respiratory tract, such as acute and chronic pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia, call attention to the underlying immune defect. Almost always the causative organisms are Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus

16. Chronic mucocutaneous candidiasis Its a hereditary disorder. It is persistent or recurring infection with Candida (a fungus) due to malfunction of T cells (lymphocytes). Because T cells malfunction, the body is less able to fight fungal infections (  candidiasis ), a yeast. It is due to a mutation in specific genes. Symptoms cause infections in mouth, scalp, skin, and nails. Membranes lining the mouth, eyelids, digestive tract, and vagina (  vaginal yeast infection ) may also be infected. Usually, this disorder is chronic, but it does not affect life span.

17. Symptoms cause infections in mouth, scalp, skin, and nails. Membranes lining the mouth, eyelids, digestive tract, and vagina (  vaginal yeast infection ) may also be infected. Usually, this disorder is chronic, but it does not affect life span.

18. DiGeorge syndrome DiGeorge syndrome is a T-cell deficiency that results from failure of development of the thymus . Thus, individuals with this syndrome have a variable loss of T cell–mediated immunity. Absence of cell-mediated immunity is caused by low numbers of T lymphocytes in the blood and lymphoid tissues and poor defense against certain fungal and viral infections.

19. DiGeorge syndrome is caused by a small germline deletion that maps to chromosome22q11, and DiGeorge syndrome is now considered a component of the 22q11 deletion syndrome. One gene in the deleted region is TBX1, which is required for development of the branchialarch and the great vessels.

20. Symptoms: C ongenital heart disorder underdeveloped or no parathyroid glands (which help regulate calcium levels in the blood). As a result, calcium levels are low, leading to muscle spasms (tetany) within 48 hours after birth. Face: unusual facial features, with low-set ears, and wide-set eyes, cleft palate. Thymus gland: missing or underdeveloped leads to low number of T cells, limiting their ability to fight many infections.

21. X-linked lymphoproliferative syndrome X-linked lymphoproliferative disease is characterized by an inability to eliminate EBV, eventually leading to fulminant infectious mononucleosis and the development of B-cell tumors . T he disease is due to mutations in the gene encoding an adapter molecule called SLAM-associated protein (SAP). SAP binds to a family of cell surface molecules involved in the activation of NKcells and T and B lymphocytes, including the signaling lymphocyte activation molecule (SLAM). Defects in SAP attenuate NK and T-cell activation and result in increased susceptibility to viral infections.

22. Ataxia-telangiectasia Ataxia telangiectasia is an autosomal-recessive disorder characterized by abnormal gait (ataxia), vascular malformations (telangiectasis), neurologic deficits, increased incidence of tumours, and immunodeficiency. The T-cell defects, which are usually less pronounced are associated with thymic hypoplasia. Patients experience upper and lower respiratory tract bacterial infections, and increasingly frequent cancers with advancing age.

23. The gene responsible for this disorder is located on chromosome 11 and encodes a protein kinase called ATM (ataxia telangiectasia mutated). In response to DNA damage (double-strand breaks)ATM activates p53 by phosphorylation, which in turn can activate cell cycle checkpoints and apoptosis in cells with damaged DNA.

24. Hyper- IgM syndrome Characterized by normal or high levels of immunoglobulin M (IgM) and decreased levels or absence of other immunoglobulins. Production of large amount of IgM >200mg/dl of polyclonal IgM as a result, people are susceptible to pyogenic infection . It may be inherited in one of the following ways: 1)As an  X-linked disorder [ mostly] 2)As an  autosomal recessive disorder

25. In this, B cells produce only IgM, not other types of immunoglobulin levels of IgM may be normal or high. Usually affect only boys. Infants with this form often develop  pneumonia , frequent sinus and lung infections during the first 2 years of life. Many children die before puberty, and those who live longer often develop cirrhosis or lymphoma. X-linked hyper-IgM syndrome

26. Severe combined immunodeficiency It is a serious, potentially fatal immunodeficiency disorder. It is congenital and can be caused by mutations in many different genes. All forms are hereditary. The most common form results from a mutation in a gene on the X (sex) chromosome (called an  X-linked disorder ) and occurs almost exclusively in boys. The x-linked SCID is due to a defect in gamma-chain of IL-2 also shared by IL-4, -7, -11 and 15, all involved in lymphocyte proliferation and/or differentiation.

27. This cause low levels of antibodies (immunoglobulins) and low or no T cells (lymphocytes). There are no T cells and because B cells cannot produce antibodies without the help of T cells, immunoglobulin levels are low. Also,  natural killer cells  do not function normally. The autosomal SCIDs arise primarily from defects in adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) genes which results is accumulation of dATP or dGTP , respectively, and cause toxicity to lymphoid stem cells

28. Mutations in recombinase-activating genes (RAG) or other components of the antigen receptor gene recombination machinery prevent the somatic gene rearrangements that are essential for the assembly of TCR and Ig genes. This blocks the development of T and B cells. An intracellular kinase called JAK3 is essential for signal transduction through cytokine receptors containing the common γ chain. Mutations of JAK3 therefore have the same effects as mutations in the γc chain.

29. Symptoms: Most develop pneumonia, persistent viral infections, thrush. All infants with this disorder have a severely underdeveloped thymus gland. If not treated, these children usually die before age 1 year.

30. Wiskott -Aldrich syndrome Hereditary characterized by abnormal antibody (immunoglobulin) production, T-cell malfunction, a low platelet count, and eczema ( patches of skin got inflammed). It results from a mutation in a gene on the X (sex) chromosome ( X-linked disorder) , which codes for a protein needed by T and B cells to function. Thus, these cells malfunction. It usually affects only male child. Platelets are small and malformed. The spleen removes and destroys them, causing the platelet count to be low.

31. Symptoms Because the number of platelets is low, bleeding problems, usually bloody diarrhea, may be the first symptom. Susceptibility to viral and bacterial infections, particularly of the RTI is increased. The risk of developing cancers (such as lymphoma and leukemia) and autoimmune disorders (such as hemolytic anemia, inflammatory bowel disease, and vasculitis) is increased. Life expectancy is shortened.

32. Chronic granulomatous disease It is inherited as an X-linked recessive disorder, in which phagocytes malfunction. occur only in boys. Sometimes this disease is also inherited as an  autosomal recessive disorder . Normally, phagocytes (neutrophils, eosinophils, monocytes, and macrophages) ingest and kill microorganisms. In chronic granulomatous disease, phagocytes can ingest but cannot produce the substances (such as hydrogen peroxide and superoxide) that kill certain bacteria and fungi.

33. Symptoms Chronic infect ions occur in the skin, lungs, lymph nodes, mouth, nose, urinary tract, and intestines. Abscesses can develop around the anus and in the lungs and liver. Children may grow slowly.

34. Chédiak-Higashi syndrome Is a very rare hereditary disorder usually inherited as an  autosomal recessive disorder. People are more susceptible to infections because phagocytes do not function normally.

35. Symptoms little or none of the pigment melanin is formed (albinism) The disorder may also cause vision problems. For example, acuity, photosensitivity, Nystagmus Also have infections in the respiratory tract, skin, and membranes lining the mouth. In about 80% of people, causing fever, jaundice, an enlarged liver and spleen, swollen lymph glands, and a tendency to bleed and bruise easily. The disorder can also affect the nervous system. Respiratory burst is normal. Once these symptoms develop, the syndrome is usually fatal within 30 months.

36. Leukocyte adhesion deficiency White blood cells (leukocytes) do not function normally. It is inherited as an  autosomal recessive disorder . White blood cells are lacking a protein on their surface. As a result, white blood cells are less able to travel to sites of infection and to kill and ingest bacteria and other foreign invaders.

37. Symptoms In severely affected infants, infections develop in soft tissues, such as the gums, skin, and muscles. No pus forms in infected areas. Infections become increasingly difficult to control. Wounds do not heal well. Often, the umbilical cord is slow to fall off, taking 3 weeks or more after birth.[ Normally, it falls off in 1 or 2 weeks after birth] Most children with severe disease die by age 5

38. Cyclic neutropenia It is marked by low numbers of circulating neutrophil . The neutropenia lasts about a week during which the patients are susceptible to infection. The defect appears to be due to poor regulation of neutrophil production.

39. Disorders of complement system Deficiency of C2 is the most common complement protein deficiency. A deficiency of C2 or C4, early components of the classical pathway, is associated with increased bacterial or viral infections. The C3 component of complement is required for both the classical and alternative pathways, and hence a deficiency of this protein results in susceptibility to serious and recurrent pyogenic infections. There is also an increased incidence of immune complex–mediated glomerulonephritis.

40. The terminal components of complement (C5, 6, 7, 8, and9) are required for the assembly of the membrane attack complex involved in the lysis of organisms. Deficiency of these late-acting components is associated with increased susceptibility to recurrent Neisseria (gonococcal and meningococcal) infections. A deficiency of C1 inhibitor (C1 INH) gives rise to hereditary angioedema . The C1 inhibitor’s targets are proteases, specifically C1r and C1s of the complement cascade, factor XII of the coagulation pathway, and the kallikrein system.

41. Although the exact nature of the bioactive compound produced in hereditary angioedema is uncertain . T hese patients have episodes of edema affecting skin and mucosal surfaces such as the larynx and the gastrointestinal tract. This may result in life-threatening asphyxia or nausea, vomiting, and diarrhea after minor trauma or emotional stress.

42. Secondary disorders Secondary immunodeficiency disorders happen when an outside source like a toxic chemical or infection attacks your body. The following can cause a secondary immunodeficiency disorder: severe burns, chemotherapy, radiation, chronic disorders such as diabetes[ diabetes = white blood cells do not function well when the blood sugar level is high ] cancer, Drugs, malnutrition. Examples of secondary immunodeficiency disorders include: AIDS, cancers of the immune system, like leukemia immune-complex diseases, like viral hepatitis multiple myeloma

43. The most serious secondary immunodeficiency is AIDS. Acquired Immunodeficiency Syndrome AIDS is caused by the retrovirus human immunodeficiency virus (HIV) and is characterized by profound immunosuppression. T hat leads to opportunistic infections, secondary neoplasms, and neurologic manifestations.

44. Epidemiology Heterosexual transmission, chiefly due to contact with members of other high-risk groups (e.g., intravenous drug users), is responsible for approximately 20% of cases in the United States. Intravenous drug users with no previous history of homosexuality are the next largest group. HIV infection of the newborn. Children of HIV-positive women are at risk for infection in utero, at birth, or t hrough breast milk. Patients with hemophilia, especially those who received large amounts of factor VIII or factor IX concentrates.

45. ETIOLOGY HIV is a non transforming human retrovirus belonging to the lentivirus family. Two genetically different but related forms of HIV, called HIV-1 and HIV-2, have been isolated from patients with AIDS. HIV-1 is the most common type associated with AIDS in the United States, Europe, and Central Africa .

46. Whereas HIV-2 causes a similar disease principally in West Africa and India. Specific tests for HIV-2 are available, and blood collected for transfusion is routinely screened for both HIV-1 and HIV-2 seropositivity

47. Pathogenesis Although HIV can infect many tissues, the major target of HIV infection is the immune system. The central nervous system (CNS) is also affected. Profound immune deficiency, primarily affecting cell mediated immunity, is the hallmark of AIDS This results chiefly from infection and subsequent death of CD4+ T cells as well as impairment in the function of surviving helper T cells, but infection of macrophages and DCs also contributes.

48. HIV enters the body through mucosal tissues and blood and first infects T cells as well as DCs and macrophages. The infection becomes established in lymphoid tissues, where the virus may remain latent for long periods. Active viral replication is associated with more infection of cells and progression to AIDS

49. HIV – infected patients who receive a transplant may experience infections similar to those seen in HIV- negative patients, but the risk of some infections is higher . These include: Tuberculosis: A latent infection that can be reactivated after transplantation. Fungal Infections : Can be a problem, especially in the early post- transplant period. Cytomegalovirus (CMV): A common post transplant complications in HIV-infected kidney transplant recipients. Coccidioidomycosis : Can result from primary infections or reactivation of a prior infection.

50. Nowadays, the vast majority of HIV- infected transplant recipients know their HIV serostatus before transplant. The efforts of transplant professionals and the release of guidelines for reducing transmission of blood-borne viruses (mainly HIV, HBV and HCV) through organ transplantation. Have facilitated this knowledge conversely, when systematic screening of donors had not yet been fully established, the proportion of transplant patients with HIV seroconversion after transplantation in the pre-HAART era was around60%. Post-Transplant Infections in HIV- infected SOT Recipients

51. Post- transplant infections are a major causes of morbidity and mortality in transplant recipients with HIV infection and serve infection was generally more frequent in HIV/HCV –coinfected SOT recipients. Post- transplant infections can be classified in to three types: health care – related infections and post- surgical infections ( e.g biliary tract, urinary tract ). Infections caused by immunosuppressive drug therapy; and infections related to complications of end-stage graft disease ( e.g. liver cirrhosis and dialysis).

52. REFERENCES Robbins & Cotran Pathologic Basis of Disease Tenth Edition vol I.

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