BMS 150 Spring_Primary Immunodeficiencies (1) PDF

Part 1: https://ccnm.ca.panopto.com/Panopto/Pages/Viewe r.aspx?id=dbfc3eaa-4cc0-45cc-8e95-aff5002deb31 Part 2: https://ccnm.ca.panopto.com/Panopto/Pages/Viewe r.aspx?id=824c45cd-b21b-4239-9f62-b01100ff4f47 Immunology Primary Immunodeficiencies BMS 150 Week...

Part 1: https://ccnm.ca.panopto.com/Panopto/Pages/Viewe r.aspx?id=dbfc3eaa-4cc0-45cc-8e95-aff5002deb31 Part 2: https://ccnm.ca.panopto.com/Panopto/Pages/Viewe r.aspx?id=824c45cd-b21b-4239-9f62-b01100ff4f47 Immunology Primary Immunodeficiencies BMS 150 Week 4 Objectives Define Immunodeficiencies Describe pathophysiology, clinical signs and treatment of Primary Immunodeficiencies: B Cell Deficiencies: Isolated IgA deficiency Common variable immunodeficiency X-linked agammaglobulinemia (Bruton’s) Hyper IgM syndrome DiGeorge syndrome (T Cell Deficiency) Severe combined immunodeficiency Innate Immunodeficiencies: Complement Deficiencies Hereditary Hemangioma Describe infectious diseases risk of systemic glucocorticoid use Immunodeficiencies Any defect in the immune response that renders an individual more susceptible to infectious diseases that would be cleared by someone who was healthy Patients with immunodeficiency diseases are more prone to contracting infections and these infections are more likely to end in long-term debilitation or death. They also have higher risk for developing autoimmunity or cancer. Primary Immunodeficiencies: Mostly inborn (genetic) and often detected in infancy or childhood (though some are detected in adulthood) Secondary Immunodeficiencies: Acquired due to external factors (e.g. infection, chemotherapy, medications…) Primary Immunodeficiencies How do people with immunodeficiencies present? The above is a generalization re: how primary immunodeficiencies affect the patient There are exceptions to the general rules presented above The table is also not comprehensive Primary immune deficiencies Most of these are relatively rare, but they are the most common among the 1° immunodeficiencies: § B Cell Deficiencies: Isolated IgA deficiency 1/600 Common variable immunodeficiency 1/50,000 X-linked agammaglobulinemia (Bruton’s) 1/250,000 Hyper IgM syndrome 1/1,000,000 § DiGeorge syndrome 1-2/2000 § Severe combined immunodeficiency 1/75,000 § Innate Immunodeficiencies: Complement Deficiencies 1/20,000 Hereditary Hemangioma 1/50,000 X-linked agamaglobulinemia Not very common – 1/250,000 population Very few of the primary immune deficiencies are common, though Pathophysiology: Inability of Pro-B cells to differentiate into Pre-B cells They can make a heavy chain variable region, but not a light chain, so they’re unable to make antibodies Due to lack of a tyrosine kinase that initiates recombination and antibody formation XLA (Bruton’s agammaglobulinemia) Clinical features Usually only males are affected (X-linked) When females express this disease, other genetic defects are thought to be in play Recurrent respiratory infections call attention to the disease Pharyngitis, sinusitis, bronchitis, pneumonia Most are gram positive bacteria that are usually destroyed by IgG opsonization and phagocytosis Diagnosis: B-cells are absent or very much decreased All immunoglobulins are depressed B-cell areas of lymphatic tissues are underdeveloped Treatment – IVIG Prognosis: in the past, most died in childhood IVIG therapy allows most people to live into their 40’s… it’s absolutely key to diagnose it and treat it early Common Variable Immunodeficiency Numerous immunological issues can be present defects in most classes of antibody secretion, inability of helper T-cells to amplify antibody production, reduced cytotoxic T-cell activity, and assorted defects in the innate immune system may be present Common feature is hypogammaglobulinemia, usually involving all antibody classes but sometimes only IgG Other diagnostic criteria – reduced B-lymphocytes, recurrent bacterial infections Uncommon—1/50,000 of the population Not necessarily a single disease, but a diagnosis of exclusion Common Variable Immunodeficiency Clinical Features: Resembles XLA – recurrent sinopulmonary infections, giardiasis, and serious enterovirus infections Can also have recurrent, severe herpes infections 20% rate of autoimmune disease Diagnosis: No other B-cell abnormality (isolated IgA, XLA) detected Reduced (but not absent) immunoglobulins (not as severely reduced as XLA) B-cell areas of lymphatic tissues are hyperplastic, usually Treatment: IVIG Prognosis: 20-year survival is high, people can live for quite a while with therapy Isolated IgA deficiency Very common – 1 in 600! Your only common primary immunodeficiency Much, much more common in Caucasians Pathogenesis: No one knows… defects in a receptor for a B-cell activating cytokine? Reduced amounts of IgA in serum, very little in secretions, but normal levels of other antibodies and lymphocytes Lymphatic tissues look pretty much normal under a slide IgA deficiency Clinical Features: Most are asymptomatic – symptoms, if they are recognized, are usually not recognized until adulthood History significant for recurrent otitis media, sinusitis, bronchitis, pneumonia, GI tract infections Like many other B-cell deficiency diseases – however, the immunodeficiency and subsequent infections are not nearly as severe Also increased incidence of autoimmunity, particularly lupus and RA A potentially deadly complication is life-threatening anaphylaxis post-blood transfusion Recognize transfused IgA as foreign Clinical pearl – the serology for detecting celiac disease is based on detection of IgA antibodies to enzymes that are involved in metabolizing gliadin IgA deficiency can result in false negatives in these celiac patients Prognosis is good Hyper-IgM Syndrome Patients make IgM but have difficulty producing IgG, IgA, and IgE Inability of helper T-cells to activate B-cells and macrophages CD40L deficit or lack of function Gene is on the X-chromosome, thus is X-linked and usually affects ??? 30% of patients have other defects – inheritance pattern is autosomal recessive in these instances Very uncommon - 1/1,000,000 live births Hyper-IgM syndrome Clinical features: Recurrent pyogenic (purulent) infections Can be in the CNS, respiratory tract, and GI tract Many viral infections Hepatitis, gastroenteritis, encephalitis, pulmonary infections These people are very immunodeficient – neutrophil counts are also decreased for unknown reasons High IgM, low on other antibodies, decreased neutrophils, decreased CD40L on T-cells can be used to diagnose Treatment & Prognosis IVIG and intense antibiotic prophylaxis Prognosis is guarded… meaning often not good (20% survival rate in those 25 and older) 22q11 deletion (DiGeorge) syndrome T-cell deficiency – most of the immunodeficiencies involve primarily B-cell defects (at least clinically) 3rd and 4th pharyngeal pouches don’t develop… So you’re short on a thymus, parathyroid glands, some thyroid tissue Can also have heart and great vessel defects Hypothesized that the T-box family of transcription factors is absent or does not function – important transcription factor for branchial/pharyngeal arch development and large vessels Loss of genetic material on chromosome 22, on the long arm Relatively common – 1-2/2000 population 22q11 deletion (DiGeorge) syndrome Clinical Features: Immunodeficiency: thymic hypoplasia results in variable loss of T-lymphocytes – low in blood and in lymphatic tissue Increased fungal and viral infections Increased autoimmunity (RA, thyroiditis) Cardiac abnormalities (especially associated with the great vessels) Craniofacial abnormalities – cleft palate, high and broad nasal bridge, long face, narrow palpebral fissures, and micrognathia Developmental delay Hypoparathyroidism… what electrolyte abnormality would this be associated with??? Very complex disorder, usually diagnosed in childhood when cardiac abnormalities are identified and treated surgically 22q11 deletion (DiGeorge) syndrome 22q11 deletion (DiGeorge) syndrome Treatment: Avoid blood products, can result in graft-vs-host disease GVD will be discussed later on Infectious disease specialist for immunotherapy, antibiotic prophylaxis Prognosis varies greatly – not everyone has every manifestation Severe Combined Immunodeficiency A multitude of etiologies, defined by: recurrent, severe infections by a wide range of pathogens C. albicans, P. jiroveci, Pseudomonas, CMV, varicella, and a ton of different types of bacteria Very severe – need bone marrow transplant or stem- cell therapies or death ensues at a young age defects in both cell-mediated and humoral immunity Occurs in ~ 1/75,000 live births Severe Combined Immunodeficiency (SCID) 50-60% of SCID is X-linked, due to mutation in the gamma-chain of a variety of cytokine receptors signal-transducing component of the receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, and IL-21 very few T-lymphocytes or NK cells… yikes Remainder is autosomal recessive due to a mutation in adenosine deaminase accumulation of deoxyadenosine and its derivatives are thought to be toxic to rapidly dividing lymphocytes RAG mutations (interferes with somatic recombination)– B- and T-cell development blocked Severe Combined Immunodeficiency (SCID) Pathological and clinical features: Pathology: small thymus with very few lymphocytes depletion of T-cell areas of other lymphatic tissues Signs and symptoms: Presents very early in life with recurrent severe infections Occasionally the mother’s T-cells are transferred across the placenta and cause graft-versus-host-disease (mom’s lymphocytes attack baby’s tissues), shows up as a generalized, morbilliform rash Innate Immunodeficiencies Complement defects: C2 deficiency – most common deficiency increased bacterial or viral infections, though many have no increased incidence of infection alternative pathway is adequate for most cases Increased risk of SLE Deficiencies of other components properdin, factor D, C3, and ? deficiencies are uncommon, but result in more severe immunosuppression Innate Immunodeficiencies Hereditary angioedema Autosomal dominant disorder, less common than the complement deficiency disorders (1 in 50,000, so still not that common) deficit in C1 inhibitor – results in: unchecked activation of the classical complement pathway increased bradykinin production (seems to be the most important molecule in pathogenesis) increased activation of certain components of the clotting cascade Innate Immunodeficiencies—Hereditary angioedema Clinical features: episodic, attacks usually become progressively more severe can be precipitated by minor trauma (pressure), stress Symptoms: severe abdominal pain – can be mistaken for serious abdominal pathology vomiting and diarrhea can also be present swelling of face, hands, legs, groin – can be life-threatening if airway is involved pleural effusions and seizures rarely occur Treatment and Prognosis can treat with C1 inhibitor from blood products – greatly improved prognosis mortality used to range between 20 – 30% Infectious Diseases Risk of Systemic Glucocorticoid Use Systemic use of glucocorticoids can increase risk of infections Increased risk with higher doses (e.g. 15-30g prednisone) and for greater than 2-4 weeks E.g. in IBD patients on corticosteroids alone, the relative risk of bacterial infections was found to be 5-fold higher 4-fold higher for other infections like strongyloidiasis and tuberculosis 1.5 fold higher for viral infections Specific Infections: Pneumocystis jiroveci pneumonia Fungal infection of the lung Combination antibiotics prophylactically or treatment Youssef et al. Rheum Dis Clin North Am. 2016 Infectious Diseases Risk of Systemic Glucocorticoid Use Herpes Zoster (Shingles) Reactivation of varicella zoster virusà painful rash Vaccinations or antiviral Tuberculosis Conversion of latent TB to active formà usually affects lungs Should be tested for before glucocorticoid treatment and treated with antibiotic (isoniazid) beforehand Strongyloidiasis A chronic parasitic infection, usually acquired through direct contact with contaminated soil (can be asymptomatic) Can persist for several decades and can reactivate with glucocorticoid exposure. Treated with antiparasitic Other opportunistic infections? Aspergillosis, nontuberculous mycobacterial disease, candidiasis, and cryptococcosis Evidence for these is less robust Youssef et al. Rheum Dis Clin North Am. 2016