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What are the primary B cell deficiencies? (3)

X-linked agammaglobulinemia
-(Bruton type)

IgA deficiency

Transient hypogamma globulinemia

Typical infections

Antibody deficiency is associated with recurrent infections with encapsulated bacteria.
-Pneumococcus
-Neisseria meningitis
-Streptococcus
-Staphylococcus

What is the defect in Brutons agammaglobulinemia? (2)

Brutons tyrosine kinase (BTK) gene is defective

Regulates c-Jun and other transcription factors that are important in cytokine gene activation.

Treatment for X-linked Brutons immunodeficiency

XLA patients need lifelong antibody replacement through monthly injections of gamma globulin (IVIG).

IgA deficiency (3)

The most common immunoglobulin deficiency. The major immunoglobulin in human saliva, nasal and bronchial fluids, and intestinal secretions, IgA guards against bacterial and viral reinfections.

IgA deficiency leads to chronic sinopulmonary (related to the paranasal sinuses and the airway of the lungs) infections, GI diseases, and other disorders.

Selective IgA deficiency is the most common congenital immune deficiency, found in about 1 in 500 individuals in the USA.

Primary IgA deficiency

IgA deficiency may be primary ,sporadic, or familial. Both serum and secretory IgA are lacking in most patients and, rarely, one or the other.

Although certain studies have reported recurrent infections in as many as 50% of IgA-deficient patients, most of these individuals are healthy. Some patients develop symptoms after an uneventful childhood and early adulthood.

Recurrent or chronic upper and lower respiratory tract infections may result in bronchiectasis or cor pulmonale in insufficiently treated patients. G lamblia infection of the GI tract is common. Other GI diseases, such as spruelike syndrome, ulcerative colitis, and Crohn disease, have been reported.

Ethnic distribution and IgA deficiency

IgA occurs in Asian persons at a rate of 1 case per 14,840-18,500 persons,

Arabs at a rate of 1 case per 142 persons

Caucasians at a rate of 1 case per 500-700 persons

African American persons at a rate of 1 case per 6000 persons.

Lab studies

IgAD is defined as an undetectable serum IgA level, traditionally measured using the low-level radial immunodiffusion method (lower limit of detection is 50 mg/mL [5 mg/dL]).

Symptoms

Tonsillitis, sinusitis, and bronchitis with extracellular encapsulated bacteria
-Haemophilus influenzae,
-Streptococcus pneumoniae

Treatment

Replacement therapy is not practical for IgAD because of the short half-life of IgA and the relative paucity of IgA in commercial immunoglobulin preparations.

Immunization with pneumococcal polysaccharide vaccine is important; however, not all patients are able to mount an immune response.

Secondary IgA deficiency

Cigarette smoking
Administration of certain drugs
-Phenytoin
-D-penicillamine
-Sulfasalazine
-Hydroxychloroquine

Transient IgAD

Infections may cause a transient IgAD. The following have been recognized as causes:
-Rubella
-Cytomegalovirus
-Toxoplasma gondii
-Congenital rubella
-Epstein-Barr virus infection

Treatment for IgA deficiency

There is no specific treatment for selective IgA deficiency.

Doctors treat bacterial infections with antibiotics, and patients with giardiasis (an infection caused by a common intestinal parasite) receive metronidazole or quinacrine hydrochloride.

What is the defect in IgA deficiency ?

The primary defect in selective IgA deficiency is related to a failure of B cells to differentiate to mature isotype-switched surface IgA-positive B cells and IgA-secreting plasma cells with appropriate stimuli.

The basis for the defect is not known.

Common variable immunodeficiency (CIVD)

A grouping that includes a number of disorders that effect older (15-35) individuals

Leads to recurrent bacterial infections

Lab studies

Patients with CVID have marked reduction in serum levels of both immunoglobulin G (IgG) and immunoglobulin A (IgA);

Half of these patients also have reduced immunoglobulin M (IgM)

B-cell number is depressed or function inhibited

What is the nature of the defect?

Decreased number and/or function of CD4+ T lymphocytes or, occasionally, to an increased number of CD8+ T lymphocytes.

Cannot stimulate B cells to mature

40% of patients with CVID, the CD40 ligand is expressed in low levels on activated T cells.

CVID frequency

The prevalence of CVID is approximately 1 case per 50,000 population.

Symptoms

Patients with CVID often have a history of recurrent infections.

The recurrent infections commonly affect the upper and lower respiratory tracts.
-Otitis media,
-Diarrhea,
-Pneumonia,
-Sinusitis

What is the cause of the diarrhea?

Persistent diarrhea and malabsorption caused by Giardia lamblia infection occur in patients with CVID.

Symptoms generally resolve after treatment with metronidazole.

Young children may fail to thrive because of the frequent infections or gastrointestinal tract disease.

Bacteria causing respiratory tract infections

Common infective organisms include
Haemophilus influenzae,
Streptococcus pneumoniae,
Moraxella catarrhalis
Staphylococcus aureus.
Pneumocystis carinii
Mycoplasma pneumoniae

Treatment

The mainstay of treatment for CVID is Ig replacement therapy. Although expensive, Ig replacement therapy stops the cycle of recurrent infections.

A dose of 400-600 mg/kg every 2-4 weeks is usually required. In patients with structural lung damage, a level of 700-800 mg/dL is required.

What is the frequency of B cell deficiencies?

Acquired B-cell disorders are far more common than genetic disorders affecting B cells. Antibody deficiency disorders comprise 50% of all primary immunodeficiencies.

The first and second most common B-cell disorders are IgA deficiency and CVID, with incidence estimated at 1 case in 700 persons and 1 case in 53,000-100,000 persons of European ancestry, respectively.

IgG subclass deficiency

IgG1

IgG2

IgG3

IgG4

IgG subclass deficiency

This is defined as a decrease of an IgG subclass greater than 2 standard deviations below the normal mean for age.

One or more IgG subclasses may be involved. This deficiency may be isolated or associated with other immunodeficiencies.

IgG1 deficiency is rare.

IgG1 deficiency

Extremely rare event

Antibodies against protein antigens
-Tetanus

IgG2 deficiency

Associated with an inability to mount an antibody response to capsular polysaccharides

Recurrent sinopulmonary infections with encapsulated bacteria
-H influenzae
-S pneumoniae.

IgG3 deficiency

Antibody response to viral infections and Moraxella catarrhalis.

Associated with recurrent sinopulmonary infections

IgG4 deficiency

Antibodies against large extracellular parasites, such as Schistosoma and Filaria

10-15% of the general population.
-It may be isolated or associated with other IgG subclass deficiencies

Treatment

In IgG subclass deficiency, most clinicians reserve IVIg for patients unable to make antibodies to both protein and polysaccharide antigens.

Treatment

Unless a patient has an impaired response to tetanus, diphtheria, and pneumococcal vaccine, IgG deficiency is not considered clinically significant. IVIG should not be used in these patients until a thorough antibiotic trial has failed to control their infections.

Hyperimmunoglobulin E (HIE) or Job syndrome

Hyperimmunoglobulin E (HIE) syndrome was first described as Job syndrome in 1966 when 2 patients were reported with
-Eczematous dermatitis,
-Recurrent staphylococcal boils,
-Hyperextensible
-Joints
-Distinctive coarse faces.


It is inherited in an autosomal-dominant manner with variable penetrance.

Patients have an inadequate inflammatory response that may delay recognition of infections

Symptoms

HIE is now well recognized as a constellation of recurrent skin and lung infections, mainly but not exclusively with

-Staphylococcus aureus
-Mucocutaneous candidiasis,

Unusual group of facial features including coarse faces.

Facial features in females

She had a history of multiple deep-seated abscesses that took months to heal after incision and drainage.

Facial features in males

Note the father's distinctive face with prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance.

Immunological defects

Deficient suppressor T-cell numbers and activity and an imbalance in helper T cell type 1 (TH1) and helper T cell type 2 (TH2)

Poor, delayed hypersensitivity response to antigens.

Chemotactic defect in neutrophils.

Defective production of interferon-gamma, a major activator of neutrophils when stimulated by interleukin (IL)-12.

Mechanism of elevated IgE

The poor production of interferon-gamma in response to IL-12 results in the marked elevation of IgE levels (by means of unopposed IL-4 action).

Treatment

No definitive therapy is available for the treatment of hyper-IgE syndrome.

The mainstay of treatment is the control of bacterial infections.

Early incision and drainage followed by the intravenous administration of antibiotics are used for cutaneous infections.

Coverage is usually aimed at Staphylococcus and Haemophilus species.

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