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Flashcards in B and T cell immunodeficiency week 3 Deck (27):
1

Of the primary immunodeficiencies, what is the most common type?

Antibody deficiencies

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2

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

3

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

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4

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

5

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.

6

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.

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7

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.

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8

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.

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9

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.

10

What is the most common type of immunodeficiency?

Selective IgA deficiency

11

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.

12

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.

13

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.

14

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

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15

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:

1. Quantitative immunoglobulins: measurement of serum IgG, A, and M concentrations by radial immunodiffusion or nephelometry. Normal values vary by age.

2. Isohemagglutinin titer: indication of IgM function. Children over 1 year old should have a titer > 1:4.

3. 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.

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16

What type of infections do patients with T-cell immunodeficiency often have? What other symtoms and diseases do they have?

Why must one be careful with transplants and live vaccines in patients with cellular immunodeficiency?

  • Chronic infections with intracellular organisms, wasting, diarrhea and graft-versus-host disease (GVHD), malignancies
  • Can have fatal responses to live vaccines
  • Graft-versus-host reactions occur when immunocompetent lymphocytes (either from blood transfusions, marrow or thymus transplants, or transplacentally from the mother in utero) are given to a histo-incompatible, immunocompromised host. The lymphocytes (graft) react against the host's allogeneic cells, and the host is unable to control the reaction.

FYI:

Pattern of Infections

  • Mycobacteria, esp. atypical and including BCG
  • Salmonella
  • Candida and Pneumocystis (fungal)
  • Herpes viruses

 

17

What is the inheritance pattern of DiGeorge syndrome? What is the chromosomal locus for this disease?

What is the cause of DiGeorge syndrome?

What are the differences btwn partial and complete DiGeorge syndrome? Which is more common?

What are the clinical features of this syndrome?

How may it be quickly diagnosed?

The majority of cases of DiGeorge syndrome are associated with defined hemizygous chromosomal deletions--> 22q11.2. Inheritance is autosomal dominant or sporadic.

A congenital disorder, DiGeorge syndrome results from arrested development of the third and fourth pharyngeal pouches during weeks 6-12 of gestation. This results in thymic hypoplasia, hypoparathyroidism, anomalies of the aortic arch and abnormal facies. Patients present with hypocalcemia/tetany due to parathyroid hormone deficiency (low PTH=low calcium=tetany, presents in the first few days of life); cardiac disease (truncus arteriosus, patent ductus, interrupted aortic arch etc.); abnormal facies (low set ears, notched pinnae, "fish mouth" with short philtrum, hypertelorism, and micrognathia); and variable immunodeficiency.

Partial DiGeorge anomaly:

  • Most frequent
  • Thymic hypoplasia
  • Normal corticomedullary differentiation
  • Normal thymic function
  • CD4 cells > 400/mm3
  • T-cell function adequate
  • Bcell numbers and function normal
  • Usually free of infections

Complete DiGeorge anomaly:

  • Uncommon
  • Thymic aplasia
  • CD4 cells < 400/mm3
  • Defective in vitro T-cell stimulation resposne to mitogens such as PHA
  • B-cell numbers normal
  • Antibody response decreased
  • Susceptible to infections: thrush, diarrhea, failure to thrive, and infections with fungal, viral, protozoan, and bacterial agents
  • Susceptible to graft vs host disease

Diagnosed immediately by lateral chest x-ray (absence of thymic shadow)

 

18

What are the screening and "advanced" tests that may be used to diagnose cellular immunity (T-cell) disorders?

Screening tests:

  • Total lymphocyte count: Patients often, but not always, have reduced lymphocyte counts associated with T cell defects.
  • Delayed hypersensitivity skin tests: A response at 48 hours to 0.05 ml intradermal injection of either tetanus toxoid, PPD, candida, trichophyton, or mumps antigen indicates intact cellular immunity. (Do not use live viruses for skin testing).

Definitive tests available to determine T cell function include:

  • T cell quantitation: T cell can be enumerated either by measuring percentage of lymphocytes reactive with monoclonal antibody reagents which detect the T-cell receptor complex (anti CD3). Normally 65-80% of total lymphocytes.
  • Response to mitogens, antigens, and allogeneic cells: These in vitro tests measure the ability of patient lymphocytes to proliferate when mixed with mitogens (phytohemagglutinin, concanavalin A, pokeweed mitogen), antigens (candida), or allogeneic lymphocytes (mixed lymphocyte culture).
  • T cell subpopulations: Monoclonal antibody reagents to T cell surface antigens allow enumeration of helper/cytotoxic (CD4:CD8) ratios (normally 2:1).

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19

What are the possible inheritance patterns of severe combined immunodeficiency (SCID)? Which is more common?

When do symptoms onset?

What part of the immune system is affected?

What kind of infections to SCID patients have? What other symptoms/clinical findings are present?

What is the prognosis?

What kind of vaccines and blood products must be avoided in these patients?

How is SCID diagnosed?

SCID

  • X-linked (most common) or autosomal recessive
  • A syndrome with a variety of underlying molecular etiologies characterized by an absence of both T and B cell immunity. B cells are often absent, although some have elevated numbers of B cells or normal B cells (see B+ SCID below). Patients are unable to make specific antibody due to the lack of T cells.
  • Because of the protective effects of maternal IgG, severe infections may not occur until 5-6 months of age.
  • Lymph nodes, tonsils, and a thymic shadow on x-rays may not be present.
  • Infection Susceptibility: All infectious organisms including live vaccine strains and opportunistic infections

  • Infections include pneumonia, otitis media, enteritis with chronic diarrhea, bacteremia, oral candidiasis, erythroderma or other skin eruption. Specific gene defects may have associated features.

  • Organisms can be bacterial, viral, fungal and protozoan
  • There is failure to thrive and wasting
  • Death usually occurs in the second year of life unless specific therapy is initiated
    • Pediatric Emergency!
  • Do not give live viral vaccines or non-irradiated blood products
  • Diagnosis: Lymphopenia in most, diminished or absent T cells in most,  poor/absent in vitro mitogen-induced T cell proliferation in all

20

What is Omenn syndrome caused by? What is it characterized by (clinical sx)?

What cells are affected?

What is the inheritance pattern?

Omenn syndrome is an autosomal recessive disease caused by hypomorphic mutations in similar genes that cause SCID (i.e., recombination activating gene (RAG)1/RAG2 deficiency: enzyme critical in Ig and TCR gene rearrangment) and is characterized by erythroderma, failure to thrive, diarrhea, severe opportunistic infections, eosinophilia, low immunoglobulins with the exception of an elevated IgE and an increase in oligoclonal T cells/memory T cells.

Because there is a deficiency in RAG1 and RAG2, there is both B and T cell deficiency.

 

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21

What is SCID: Adenosine deaminase deficiency caused by?

What cells are affected?

What is the inheritance pattern?

Adenosine deaminase deficiency (ADA) deficiency is an autosomal recessive disease due to a lack of the enzyme adenosine deaminase. This deficiency results in an accumulation of deoxyadenosine, which, in turn, leads to accumulation of dATP in all cells, which inhibits ribonucleotide reductase and prevents DNA synthesis. This is an issue since B and T-cells are mitotically active during infection, and development. Also deoxyadenosine leads to an increase in S-adenosylhomocysteine. Since the enzyme adenosine deaminase is important in the purine salvage pathway; both substances are toxic to immature lymphocytes, which thus fail to mature. Purine nucleoside phosphorylase defeincies have similar effects.

T cells, B-cells, and NK cells are all affected.

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22

What is the inheritance pattern for SCID caused by Artemis deficiency?

What does Artemis do?

What cells are affected in SCID of this cause?

Mutations in the gene for Artemis cause a rare form of autosomal recessive SCID. Artemis is protein in the pathway that mediates repair of DNA double-strand breaks by nonhomologous end-joining– this process is required for T cell and B cell V(D)J recombination. Artemis interacts with DNA and plays a role in opening of the DNA hairpin that is formed following double-stranded breaks introduced by RAG.

T and B cells are both affected.

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23

What are the two types of X-linked SCID? Which is more common?

What cells are affected?

More common form of X-linked SCID is due to lack of common gamma chain gene for used in for several interleukins including IL-2 (see Cyokine and Cyokine receptor lecture). T and NK cells are affected.

The other less common form is due to deficiency of the alpha subunit of the IL-7 receptor. IL-7 signaling is important for T-cell development so these cells are affected. Remember from the immune memory lecture that IL-7 is important in the early development of T-cells and is required for memory T-cells.

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24

What are treatments for SCID?

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Without immunoreconstitution, SCID patients usually die at 12-24 months from infection. Previously, transplants of fetal liver, fetal thymus, cultured thymic epithelium or HLA-identical bone marrow were used with varying degrees of success. Recently, haploidentical parental marrow depleted of T cells with monoclonal antibodies or lectins has been successfully used, extending the potential of bone marrow-transplantation to reconstitute patients with SCID. Stem cell transplant from HLA – matched umbilical cord blood has proven to be successful. ADA deficiency has also been treated by replacement with polyethylene glycol-modified bovine ADA and by gene therapy.

Curative:

  • Stem cell transplantation
  • Gene therapy (ADA, XL-SCID) Experimental

Adjuvant:

  • Enzyme replacement (PEG-ADA)
  • Prophylactic antibiotics
  • IVIG
  • Avoidance live viral vaccines
  • Irradiation of blood products
  • CMV negative blood products only

25

What is the inheritance pattern for Wiskott-Aldrich syndrome (WAS)?

What symptoms do these patients present with?

What are the clinical and laboratory findings? What cells are affected?

What infections is WAS associated with? When do symptoms onset?

What do older patients with WAS tend to develop?

What causes WAS? How is WAS treated?

Patients with this X-linked disorder present with thrombocytopenia, severe eczema, and recurrent infections (TIE: thrombocytopenia, infections, eczema). Thrombocytopenia is usually present at birth and may lead to bleeding; a characteristic finding is that the platelets (and lymphocytes) in WAS are small in size. Infections are often due to pyogenic bacteria (H. influenzae, S. pneumoniae, N. meningitis) with an onset at 5-6 months of age. The eczema is often secondarily infected and may be associated with other allergic manifestations. Older patients develop malignancies (lymphoma, leukemia) as well as infections with non-bacterial organisms.

Laboratory studies demonstrate elevated IgE and IgA, reduced IgM, low isohemaglutinins, absent antibody response to polysaccharide antigens and initially normal T cell immunity which often deteriorates with age. Morbidity and mortality is usually due to bleeding, infection, or malignancy. Etiology is a defect in the WAS protein, called WASp. Its function is associated with the actin cytoskeleton and plays a role in cell signaling. Mutation affects platelets, T-cells, dendritic cells and B-cells.

Splenectomy may be recommended for thrombocytopenia. Bone marrow transplant can be used to treat severe cases.

26

What is the inheritance pattern of Ataxia telangiectasia?

What are the symptoms and clinical findings? When do they present? What type of infections do they get?

What disease is associated with ataxia telangiectasia?

What do the laboratory studies of these patients look like?

What is the cause of this disorder?

Explain these patients sensitivity to radiation.

This is an autosomal recessive syndrome involving multiple organ systems---> neurologic, immunologic, endocrine, hepatic and cutaneous abnormalities. Patients usually initially present with ataxia and difficulties walking which begin soon after patients start walking. Patients subsequently develop telangiectasia of the conjunctivae (btwn 3 and 6 years of age), sinopulmonary infections with viral and bacterial pathogens, and increasing neurologic deterioration with choreoathetosis, dysconjugate gaze, and incapacitating ataxia.

There is a high incidence of lymphoid malignancy in patients who do not succumb to infections and respiratory difficulties. Increased risk of malignancies has also been described in heterozygotes.

Laboratory studies reveal an elevated alpha-fetoprotein in all patients, IgA deficiency in 40% of the patients, and variable T cell immunodeficiency, with defects in T helper function. Patients have defective DNA repair (reason for radiation sensitivity), and many have chromosomal abnormalities. The defective gene has been identified and is a due to a defect in an ATM gene, a homologue of Phospho-Inositol-3 kinase, an enzyme related to signal transduction.

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27

What are causes of secondary immunodeficiency?

Both T and B cell defects may be found in association with other disorders. Important to rule out other etiologies of immunodeficiency.

Secondary causes of immunodeficiency:

  • Malignancies
  • Viral and mycobacterial infections
  • Malnutrition
  • Uremia
  • Splenectomy
  • Protein-losing enteropathy
  • Nephrotic syndrome
  • Prematurity
  • Medications