B and T cell immunodeficiency week 3 Flashcards
Of the primary immunodeficiencies, what is the most common type?
Antibody deficiencies
What are some of the warning signs of immunodeficiency disorders?
The presence of immunodeficiency disorders should be considered in evaluating patients with susceptibility to infections. Give examples of these circumstances/disorders/diseases.
When to suspect an immunodeficiency
Patients with an immunodeficiency most commonly present with a history of chronic, recurrent, or unusual infections. However, specific disorders may be associated with suggestive history or physical findings. Some features which suggest immunodeficiency include:
- Chronic infection
- Recurrent infection
- Infections with unusual infectious agents
- Incomplete clearing of microbes between episodes of infection or incomplete response to treatment
Additional clinical findings which may be important:
- Skin rash (eczema, etc.)
- Diarrhea (chronic or prolonged)
- Growth failure (failure to thrive)
- Hepatosplenomegaly
- Recurrent abscesses
- Recurrent osteomyelitis
The presence of these disorders should be considered in evaluating the patient with susceptibility to infection:
- Circulatory disorders: sickle cell disease, diabetes, nephrosis, congenital cardiac defects
- Obstructive disorders: ureteral or urethral stenosis, bronchial asthma, allergic rhinitis, blocked Eustachian tubes, cystic fibrosis
- Integument defects: eczema, burns, skull fractures, midline sinus tracts, immotile cilia
- Foreign bodies: ventricular shunts, central venous catheter, artificial heart valves, urinary catheter, aspirated foreign bodies
- Secondary causes: malnutrition, prematurity, lymphoma, splenectomy, immunosuppressive therapy, protein-losing enteropathy, uremia
Describe the histopathology, laboratory abnormalities, and common infectious consequences of the following types of immunodeficiencies:
B cell deficiencies
T cell deficiencis
Innate immune deficiencies
figure from pg 4 of course notes, slide 16 of PP
In which sex are immunodeficiency disorders more common? Why?
Immunodeficiencies are generally more common in males than females. (many are X-linked)
Almost half of the patients with immunodeficiencies are diagnosed before 5 years of age. About 50% of immunodeficiencies are B-cell disorders, 30% T-cell or combined T-B cell disorders, 18% phagocytic cell disorders, and 2% complement disorders
What types of infections do patients with B-cell disoders (hypogammaglobulinemia) often present with? What are their symptoms?
What diseases are B-cell disorders associated with?
B-cell Dysfunction:
- Recurrent upper and lower respiratory infections (most common presenting symptom!)
- Severe bacterial infections with encapsulated bacteria
- Paucity of lymph nodes and tonsils
- Immune cytopenias
- Autoimmunity
- GI tract infections also common (giardia, enterovirus) —-> Diarrhea and malabsorption
- Malignances
Clinical Presentation of antibody deficiency: Patients with hypogammaglobulinemia typically have sinopulmonary infections (e.g. sinusitis, bronchitis, pneumonia, otitis media) due to pyogenic encapsulated bacteria such as Streptococcus pneumoniae, Hemophilus influenzae, and Streptococcus pyogenes. Conjunctivitis, dermatitis and malabsorption (often associated with giardiasis or other protozoa) are common. Meningitis, septicemia and osteomyelitis are less common, but occur. In a few patients with hypogammaglobulinemia, especially the X-linked infantile form, viral infections with echovirus, enteroviruses, polio, and hepatitis as well as Pneumocystis infections have been reported. There appears to be a unique susceptibility to mycoplasma and ureaplasma species. There may be autoimmunity or increased malignancies in some forms of antibody deficiency.
What is the inheritance pattern for Bruton’s disease? What is the chromosomal location for the cause of this disorder? What causes Bruton’s disease?
What is the time of onset of this disorder and why?
What types of infections present with this disease?
What do the laboratory studies show for this disease?
How is it diagnosed?
How is it treated?
This disease is also known as X-linked agammaglobulinemia.
In 1952 Bruton described the first boy with this X-linked syndrome. Clinically, patients have recurrent sinopulmonary infections, conjunctivitis, dermatitis, and malabsorption, often with an onset after 5-6 months of age (after mothers’ IgG levels wane). On physical exam, lymph nodes are usually not present.
Laboratory studies show markedly reduced immunoglobulins (IgG <200 mg/dl, total Immunoglobulins<250 mg/dl) with IgM, IgA, IgD, and IgE either quite low or absent. B cells < 2% of lymphocytes (~ 0.05-0.3%)/ Normal T cell number and function. No circulating B cells or plasma cells are found. Some pre-B cells with cytoplasmic mu heavy chains are present, but do not secrete immunoglobulin. The block, therefore, lies between the pre-B cells and B cell due to a failure to properly translocate VH genes in the pre-B cells. The gene defect has been mapped to a gene called btk (Bruton’s tyrosine kinase) on the long arm of the X-chromosome (at Xq22). Patient with this condition are subject to recurrent infections; especially to common extracellular bacterial pathogens:
Infection Susceptibility: pyogenic infections, viral meningo-encephalitis, vaccine strain poliomyelitis,mycoplasma arthritis encephalitis
Treatment includes:
- antibiotics
- intravenous gamma globulin
- chest physiotherapy.
The major complications are severe infections and bronchiectasis leading to chronic lung disease.
What is physiologic hypogammaglobulinemia?
When does it occur?
When do infants begin producing IgG?
Why are premature infants especially prone to this condition?
It is important to relate immunoglobulin levels in patients to age-related normal values. Infants in utero receive maternal IgG transplacentally, but do not make significant amounts of immunoglobulins themselves until after birth (5-6 months of age). As the maternal IgG disappears, there is a period between 4-6 months of age where it is normal for infants to have “low” IgG levels until they start producing IgG themselves. This represents a normal developmental stage (“physiologic nadir”). Premature infants are especially prone to thiscondition. Premature delivery prevents the neonate from receiving the normal amount of transplacental IgG, which occurs largely in the third trimester.
What is transient hypogammaglobulinemia? When does it occur and why?
What symptoms do these patients present with?
What do their laboratory studies look like?
Explain what their ability is like to synthesize specific antibodies.
How are these patients treated? What is the recommendation on administration of live viral vaccines?
What are possible etiologies?
Transient Hypogammaglobulinemia
This disorder can be differentiated from the X-linked form (Bruton’s) because it appears in both sexes.
Clinically, patients with this syndrome often are asymptomatic. A few patients may have recurrent respiratory infections, with an onset at 5-6 months of age. Levels may be low enough to cause same infections as in XLA. Molecular testing for Btk mutations recommended to differentiate.
Laboratory studies reveal an IgG of <200 mg/dl; IgM and IgA are often normal. Circulating B cells are present, and patients often can make specific antibody in response to immunization even before their immunoglobulin values normalize. These patients can synthesize natural antibodies to ABO blood groups (isohemagglutinins), tetanus and diptheria toxoids. Over a period of months these patients begin to synthesize normal amounts of immunoglobulins, although in a few this does not occur until 2 years of age.
B cells are present, and IgM and IgA are often present. Quantitative immunoglobulins should be determined every 3-4 months and gamma globulin replacement should be given only if the patient is having severe infections. Live viral vaccines should not be given until Ig levels are adequate.
Possible etiologies include transplacental maternal antibodies against fetal allotypic determinants or a lack of helper cells. Decreased numbers of CD4 (helper) lymphocytes, and in vitro immunoglobulin synthesis have been reported in patients with transient hypogammaglobulinemia.
What sex is typically affected by common variable immunodeficiency (CVID)? When in life does this disease typically onset?
What symptoms do these patients typically present with? What dieases are associated with CVID?
What do their laboratory studies look like? How is CVID diagnosed?
How is CVID treated?
Common variable immunodeficiency (CVID)
This variable syndrome of acquired hypogammaglobulinemia affects both sexes, with an onset often in 20s and 30s.
Clinically, patients develop sinopulmonary infections, malabsorption often associated with giardiasis and autoimmune disorders (arthritis, lupus, idiopathic thrombocytic purpura [ITP] etc.). Unlike X-linked agammaglobulinemia, patients with CVID may have lymphadenopathy and splenomegaly.
Clinical Features: Recurrent sinopulmonary infections, bronchiectasis, diarrhea, arthritis, giardiasis, autoimmunity (20%), asthma (10%), lymphoproliferative disease, gastric CA and lymphoma.
Affected patients have an increased incidence of malignancies. Incidence of CVID is not exactly known and is estimated in 1:30,000 to 1:50,000, but is underdiagnosed and delay in diagnosis is common.
Laboratory studies reveal an IgG of <250 mg/dl and total Ig of <300 mg/dl. often IgA and IgM are low. Slow decline in all classes of immunoglobulin. There must be a decrease in IgG along with at least one of the othermajor isotypes. B cells are present, but patients are unable to make specific antibody in response to immunization and isohemagglutinin titers are low to absent—> decreased levels of plasma cells.
T cell function may be normal, but some patients (up to 40%) have mildly reduced T cell function initially which may deteriorate with time. The etiology of CVID remains largely unknown.
Treatment includes intravenous gamma globulin, antibiotics and frequent monitoring for the development of autoimmune disease or malignancy.
What is the most common type of immunodeficiency?
Selective IgA deficiency
What sex does IgA deficiency predominantly affect? What is the inheritance?
What Ab may also be deficient in pts with IgA deficiency?
What are the symptoms of patients with IgA deficiency?
What diseases/disorders are associated with it?
What are the laboratory values for patients with IgA deficiency?
What can pts with this disease have false negative and positive testing for?
How is it treated? How must blood transfusions to patients with this disease be handled?
Selective IgA deficiency
This is the most common form of immunodeficiency with an incidence of 1 in 700 to 1 in 400 live births. It affects both men and women with variable inheritance. The clinical abnormalities associated with IgA deficiency are a spectrum and most patients are asymptomatic.
Others may have recurrent sinopulmonary infections, an increased incidence of allergies and asthma, gastrointestinal disorders (celiac disease, inflammatory bowel disease, pernicious anemia), and autoimmune diseases (lupus, rheumatoid arthritis).
Laboratory studies demonstrate an IgA level of less than 5 mg/dl; other immunoglobulins and T cell immunity are normal (although there may be an associated decrease in IgG2—>15% of cases associated with IgG subgroup deficiency).
Regulatory T lymphocytes which selectively block IgA production have been demonstrated in some patients. It is important to remember patients with IgA deficiency can have false negative testing for celiac (ie: anti IgA TTG) and false positive tests due to increased heterophile antibodies (ie: pregnancy tests or ELISA assays).
There is no direct treatment. Anaphylactic reactions to gamma globulin have been reported, presumably due to antibodies against traces of IgA found in gamma globulin. Similarly, IgA deficient patients who require transfusions may need to receive either washed, packed red cells or blood from another IgA deficient patient with the same blood type if their IgA levels are undetectable. Antibiotics should be used aggressively to treat infections. Patients should be monitored for the development of autoimmune disorders.
What is the prevalence of IgG subclass deficiency? What is the significance of IgG subclass deficiency?
What are the symptoms of people with IgG subclass deficiency?
There are four IgG subclasses which vary in their structure and function. Of total serum IgG, IgG1 is 65%, IgG2 is 23%, IgG3 is 8%, and IgG4 is 4%. There is evidence of differential antibody isotype response; for example, antibodies to proteins such as tetanus toxoid are largely IgG1 while those to polysaccharides are largely IgG2. Since IgG2, IgG3, and IgG4 make up only 35% of the total IgG, deficiencies may not be picked up by measuring only total IgG concentrations. Patients may have isolated IgG subclass deficiencies (up to 20% of population) or they may be present in association with other immunological abnormalities such as IgA deficiency (IgG2). Many people with subclass deficiency do not have increased infection.
IgG subclass deficiency is not clinically important but if have a dysfunction in certain subclass could have issues with response to vaccines—> IgG1 primarily binds to tetanus toxoid for example.
What is the inheritance pattern for Selective IgM deficiency?
What is the issue with the immune system in this disorder?
What type of infections do pts have with this disease?
Selective IgM deficiency is an autosomal recessive disorder in which there are normal numbers of IgM-bearing B cells which are unable to develop into plasma cells. Patients have meningitis and other severe infections.
What is the cause of X-linked hyper IgM syndrome?
What are the symptoms/effects of this disorder?
What is the histopathology?
What is autosomal recessive hyper IgM syndrome due to? What physical exam finding coincides with it and why?
X-linked Hyper IgM Syndrome (IgG, IgA and IgE deficiency with increased IgM) is an X-linked disease in which class switching to IgG, IgA, or IgE does not take place. Affected boys have bacterial infections and opportunistic infections as well as IgM autoantibodies against blood elements such as red cells and platelets develop. The defect is a mutation in the CD40 Ligand on T cells, which results in a failure to deliver the class switching signals affinity maturation and memory B-cell formation via the CD40 molecule on activated B cells. Lymphoid tissue lacks germinal centers where these B-cell events occur.
Autosomal recessive Hyper IgM syndrome (types HIGM 2,3,4,5) are due to mutations in other genes involved in class switching or antibody formation (AID, UNG, NEMO, CD40). Lymphadenopathy is a feature since the B cells respond to the T cell help by forming germinal centers in the lymph nodes and proliferating. B-cells can proliferate but are unable to class switch—->lymphadenopathy
What screening tests may be performed to diagnose B-cell function?
What are the definitive or “advanced” tests for B-cell function?
Laboratory Evaluation of Hypogammaglobulinemia
Screening tests for B cell function include:
- Quantitative immunoglobulins: measurement of serum IgG, A, and M concentrations by radial immunodiffusion or nephelometry. Normal values vary by age.
- Isohemagglutinin titer: indication of IgM function. Children over 1 year old should have a titer > 1:4.
- IgG subclasses: quantitation of serum IgG 1-4
Definitive tests for B cell function include:
- B cell quantification: measurement of circulating B cell number by immunofluorescence. Normal values are 5-15% of total lymphocytes.
- Specific antibody response: measurement of increase in antibody following immunization with protein antigens (tetanus, diphtheria, KLH), bacteriophage φX174, or polysaccharide antigens (pneumococcal vaccine).
- Serum protein electrophoresis and/or immunoelectrophoresis: identification of monoclonal proteins and immunoglobulin class and light chain imbalance.
- In vitro immunoglobulin synthesis: research technique to study T helper/regulatory effects on immunoglobulin synthesis or B cell function in vitro.
o Because patients presenting with recurrent infections can have immunodeficiencies of other systems, evaluation of T cell, complement,and phagocytic function should be considered on an individual basis.