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Terms in this set (35)
What is the definition of a primary immunodeficiency?
Absence or failure of normal function of one or more elements of the immune system. They are usually present at birth.
What are the general features of a patient with primary immunodeficiency?
Recurrent infections, especially infections with unusual organisms of low virulence. And these symptoms present early in life. These are primarily inherited (Recessive or X-linked). Genetically, it is a single gene defect, usually due to a missense mutation.
If the patient had a problem with their humoral immunity, what kind of infections are they prone to?
Encapsulated pyogenic bacterial infections. A majority of primary immunodeficiencies are problems with antibody production.
If the patient had a problem with cell-mediated immunity, what kind of infections are they prone to?
Fungi, protozoa, and viruses
What system is most commonly effected in patients with primary immunodeficiencies?
What are some examples of Primary B Cell/Antibody Deficiencies?
Transient hypogammaglobulinemia of infancy. X=linked hypogammaglobulinemia or agammaglobulinema (Bruton's). Selective IgA deficiency. Hyper IgM syndrome. Common variable immunodeficiency, which is ACQUIRED not inherited.
What exactly is the pathogenesis of transient hypogammaglobulinemia?
At birth normally the infant has IgG levels equivalent to the mother's levels. Normally infections do not occur. Between 3-6 months is a phase of "physiological hypogammaglobulinemia". There is a physiological trough of low IgG.
What exactly is the pathogenesis of X-linked agammaglobulinemia?
It is caused by a mutation in gene Bruton's tyrosine kinase (Btk), the long arm of the X chromosome. The symptom severity depends on the location of the mutation. There is a problem in the maturation of pre-B cells to immature B cells.
What would you be looking for in a patient with X-linked agammaglobulinemia?
A male child, less than 6 months of age, with no tonsils, very little to no Ig in the blood, and low number of B cells with normal T cells and phagocytes. Extreme susceptibility to pyogenic bacterial infections.
How do you treat an infant boy with X-linked agammaglobulinemia?
Appropriate antibiotics, intravenous IgG for passive immunization (this ensures survival past 4th decade)
What is the most common primary immunodeficiency, and what are its characteristic features?
Selective IgA deficiency. There are decreased to no IgA serum levels. Normal T cells and phagocytes. May also have decreased IgG 2/4 levels. Inheritance most likely MHC-linked.
What are the clinical associations of selective IgA deficiency?
Bacterial and viral sinopulmonary, GI, and eye infections, Type III immune complex disease, and Type I hypersensitivity reactions, as well as some autoimmune diseases.
How do you treat someone with selective IgA deficiency?
Use appropriate antibiotics for infections. Do NOT USE intravenous IgA. They will develop serum sickness.
What is Hyper-IgM Syndrome?
Antibody deficiency with high IgM levels. It is an X-linked disease, and males are primarily affected. Macrophage function is also impaired. There is increased susceptibility to Pneumocystis jiroveci infection (aka Pneumocystis carinii pneumonia or PCP)
What is the pathogenesis of Hyper-IgM syndrome?
It results from the failure of CD40 ligand (CD40L) expression on CD4 cells; therefore, antibody class switching is not triggered in the B cells.
What is Common Variable Immunodeficiency?
A condition acquired in the 2nd and 3rd decade of life (not hereditary). There are decreased IgG levels, and 80% have B cells that do not function properly and are immature. May be related to EBV infection. Higher risk for developing lymphoma. Susceptible to pyogenic bacterial infections and intestinal protozoan infections. And many develop AUTOIMMUNE PERNICIOUS ANEMIA, Vit. B12 deficiency secondary to lack of intrinsic factor.
How do you treat a patient with Common Variable Immunodeficiency?
Use appropriate antibiotics and antiparasitic agents. And you give intravenous immune globulin.
What should you know about Primary T-Cell/CMI deficiencies?
These patients will be susceptible to opportunistic infections, and a broader range of infections that B-cell deficiency pts.
What kind of organisms cause infections in T-Cell deficiencies?
Intracellular microorganisms. Viruses (VZ/herpes zoster, CMV, EBV), Protozoa (Cryptosporidium, Toxoplasma), Mycobacteria, Fungal (Candida, Pneumocystis), Bacteria: Gram neg enterics, Gram pos polysaccaride encapsulated (seen in B cell deficiencies).
Describe the pathogenesis of Chromosome 22q11.2 Deletion Syndrome.
It is an autosomal dominantly inherited deletion of chromosome 22q11.2 in 90% of patients. It is a developmental defect during embryogenesis. There is a defect of the 3rd and 4th pharyngeal pouches. Results in DiGeorge Syndrome and Velocardiofacial Syndrome.
Describe DiGeorge Syndrome.
There is thymic hypoplasia, leading to T-cell deficiency. Parathyroid hypoplasia, leading to hypocalcemic tetany and seizures through PTH deficiency. There are cardiac malformations affecting the outflow tract, CHF. Mild facial anomalies. Characteristic features include a non-functional thymus, few or no T cells, B cells present but of variable function.
Describe Velocardiofacial Syndrome.
Low ears, wide and slanting down eyes, short philtrum, cleft palate, bifid uvula, fish mouth. The patients have cardiac anomalies, developmental delay, and hyperactivity.
What kind of infections do Chromosome 22q11.2 Deletion pts. have? How do you treat them?
Recurrent bacterial, VIRAL, and FUNGAL infections. Use appropriate agents to treat infections. Bone marrow transplant with mature T cells. Fetal thymic transplant.
Describe Wiskott-Aldrich Syndrome.
X-linked immunodeficiency, there is a mutation WASp gene on short arm of the X chromosome. Encodes for a cytoskeletal glycoprotein (sialophorin = CD43 = WASp) in lymphoid cells. The syndrome affects both T cells and B cells. There is IgM deficiency and a decreased number of platelets.
What are the clinical features of Wiskott-Aldrich Syndrome?
Thrombocytopenia, which increases tendency to bleed (form petechiae and purpura) and bruise (ecchymosis). The patients also have severe eczema (atopic dermatitis) with recurrent pyogenic bacterial infections and opportunistic infections.
What is the treatment for Wiskott-Aldrich Syndrome?
Platelet transfusion or splenectomy for the bleeding. Antibiotics and IV immune globulin for the infections. And bath oils, moisturizing creams and avoidance of certain foods for the eczema. Bone marrow/stem cell transplantation is curative.
Chromosome 22q11.2 deletion syndrome and Wiskott-Aldrich syndrome are examples of combined immunodeficiency diseases. What are two main examples of SCIDs?
#1 is X-linked SCID, #2 adenosine deaminase (ADA) deficiency, autosomal recessive SCID.
Describe SCIDs in general.
Diverse group of disorders (>10 different genes, 4 phenotypes). There is absence of T cell and B cell immunity. Individuals die within 1st year from overwhelming infections. By 6 months, because they develop candidiasis, pneumocystic pneumonia, and diarrhea (rotavirus) -> FTT (failure to thrive). There is also decreased lymphoid tissues, empty or severely depleted of lymphocytes. They have NO T-cells, and the B-cells are non-functional.
What is the treatment for SCIDs?
Antibiotics, prophylaxis of Pneumocystis jirovecii (trimethoprim-sulfamethoxazole), IV immune globulin. You can cure it with a bone marrow transplant.
What is the most common form of SCID?
X-linked SCID. There is a defect in the T-cells, they lack the gamma chain of the IL-2 receptor essential for the T-cell development. This is a severe disease. There is no IgG.
What is the 2nd most common form of SCID?
Adenosine deaminase (ADA) deficiency. It is the most common autosomal recessive SCID (20%).
What is the pathogenesis of ADA deficiency?
It is a defective enzyme of the salvage pathway of purine metabolism, which catalyzes deamination of adenosine and deoxyadenosine. Accumulation of deoxyadenosine and deoxy-ATP, which inhibit DNA synthesis, which then leads to apoptosis of precursors for B, T, and NK cells. This results in abnormal bone development.
What is the treatment for ADA deficiency?
This is the first human disease to be treated with gene therapy, using a viral vector containing the ADA gene. Give injections of polyethylene glycol-modified bovine ADA, which leads to bone marrow transplantation.
What would be the common defects in complement?
Clearance of immune-complexes - C1, C4,
, deficiencies, which lead to immune-complex diseases like SLE. There might be defects in C3, decreasing opsonization, which increases the risk of encapsulated bacterial infections. There also might be defects in C5-9 (MAC), which increases the risk of recurrent disseminated Neisseria infections.
Name some conditions with defects in phagocytic function.
CGD - there is a defect in NADPH oxidase. Phagocytes cannot produce oxygen, which impairs their killing function.
Chediak-Higashi syndrome - there is a defect in vesicle fusion, which leads to impaired phagocytosis due the inability of endosomes to fuse with lysosomes. This leads to recurrent and persistent bacterial infections.
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