Chapter 31: Primary Immunodeficiency

SIGNIFICANCE OF IMMUNODEFICIENCY:
Two types of immunodeficiency present: 1. Primary immunodeficiency: Has a genetic basis and is rare.

2. Secondary immunodeficiency: Caused by lesions outside the immune system; treating the external problem will improve the immune response.

INFECTIONS PROVIDE CLUES TO THE TYPE OF IMMUNODEFICIENCY:

Healthy individuals experience infections; and this is true in early life when immunity to common pathogens has not developed. Repeated or unusual infection is an important sign of immunodeficiency and the type of infection gives clues to the cause and degree of immunodeficiency. Examples: Repeated infection with encapsulated bacteria is a sign of defective antibody production. Antibody (IgG and IgA) is the main defense against respiratory tract infection, and antibody deficiency causes recurrent respiratory infection caused by Pneumococcus or Haemophilus spp., which leads to irreversible damage to the bronchi: bronchiectasis. Infections with staphylococci, gram-negative bacteria, and fungi are characteristic of a reduced number or abnormal function of phagocytes. Terminal (late) complement defects predispose to meningitis caused by Neisseria meningitidis. Defects in T cells or macrophages predispose to infection with intracellular organisms such as protozoa, viruses, and intracellular bacteria, including mycobacteria.

Reactivation of latent herpes virus infection is particularly linked to T-cell immunodeficiency, so

recurrent attacks of cold sores (Herpes simplex) or shingles (Herpes varicella zoster) may suggest mild immunodeficiency.

Herpesvirus-induced tumors, [Kaposi's sarcoma (Human herpes virus 8) and non-Hodgkin's

lymphoma (Epstein-Barr virus)], are characteristic of T-cell dysfunction.

Mycobacterium tuberculosis is a virulent organism causing lung infection in immunocompetent

people. In mild T-cell immunodeficiency, the same organism spreads outside the lungs. More severe immunodeficiency predisposes to widespread infection with mycobacteria of low virulence normally found in the environment (e.g., Mycobacterium avium intracellulare complex).

TAQAROB 1/6

 CAUSES OF PRIMARY IMMUNODEFICIENCY: (refer to fig 31.2 page 254)

The causes of primary immunodeficiencies can be classified as: 1. Mutations: rare, affect any part of the immune system and cause severe disease. 2. Polymorphisms: very common traits; affect any part of the immune system and cause a moderate increased risk for infection. 3. Polygenic disorders: relatively common, affect mainly antibodies and cause severe disease.

Mutations and immunodeficiency: (refer to fig31.3 page 255) More than 100 mutations leading to immune deficiency are known. Many mutations result in severe combined immunodeficiency (SCID), which refers to a group of disorders affecting both T and B cells.

SCID is the most severe type of primary immunodeficiency and can be caused by:
1. 2. 3. Cytokine chain receptor defects (X-linked). Rag mutations (Autosomally inherited). Mutations in Zap-70.

The DiGeorge syndrome is caused by a large part of chromosome 22 being translocated to other chromosomes. Polymorphisms and immunodeficiency:

TAQAROB 2/6

 Genetic polymorphisms are alleles (different forms) of the same gene occurring at a single locus in at least 1% of the population. Human leukocyte antigen (HLA) alleles are polymorphic and affect the outcome of infections, including hepatitis B, hepatitis C, and HIV.

Individuals with HLA alleles that are unable to bind viral peptides have a worse outcome.
Polymorphisms of chemokines and their receptors associated with risk of HIV.

Polymorphisms in MBL and complement affect the risk for infections.

Polymorphisms persist in different frequencies in different populations, affected by prevalent infections. [The hemoglobin S polymorphism (sickle cell anemia) protects against malaria and is more common in populations living in, or with origin in, malarious zones]. Polygenic disorders: Polygenic disorders are caused by the interaction of several genes, with a contribution from environmental factors. Common variable immunodeficiency (CVID) and IgA, IgG2, and specific antibody deficiency are relatively common polygenic disorders affecting mainly antibody production. IgA deficiency affects about 1 in 600 people, but infections are only seen in about one third of patients. Celiac disease is more common in patients with IgA deficiency. CVID occurs in about 1 in 20,000 young people, affecting men and women equally. CVID is the most common primary immunodeficiency requiring treatment.

Patients have low levels of total IgG. CVID causes recurrent bouts of infection of the respiratory tract, starting in early adult life.
Infections involving the gut, skin, and nervous system also occur.

Autoimmunity is common in CVID and frequently includes pernicious anemia and thyroid
disease, arthritis, and immune thrombocytopenia.

Although 25% of patients have a family history of either CVID or IgA deficiency, environmental
factors are also important. Anti-rheumatic and anticonvulsant drugs can precipitate both IgA deficiency and CVID. . Specific antibody deficiency is often seen transiently during infancy and permanently following splenectomy. IgG2 deficiency: The affected individuals have a tendency to develop recurrent infections with Pneumococcus or Haemophilus spp.

TAQAROB 3/6

 IgG2 is a subclass of IgG produced in response to polysaccharide antigens by B cells in the

spleen (B-1 cells) without T-cell help.

DIAGNOSIS:
Because children with SCID have defective T cells and B cells, they develop infections in the first few weeks of life. Children with SCID often have unusual or recurrent infection, failure to thrive, diarrhea, unusual rashes, a family history of neonatal death or of consanguinity, and a very low total lymphocyte count (below 1 109/L [106/ml]). Antibody deficiency presents later in life because babies are born with maternal Ig transferred across the placenta. This protects the patient for the first few months of life. Some forms of antibody deficiency (e.g., CVID) does not present until adulthood.

IgG, IgA, and IgM should be measured. In patients with low levels of Igs, causes of secondary immunodeficiency, such as protein loss
from the gut or kidneys, should be excluded. If total Igs are normal, IgG subclasses and specific antibodies against Haemophilus and Pneumococcus spp. should be measured. If these tests are all normal, it is important to check that there are no problems with complement or neutrophil function (e.g., chronic granulomatous disease) before concluding that there is no immunodeficiency. Genetic Testing Testing for mutations is difficult because each affected family can carry a unique sequence. Once a preliminary diagnosis of a disease caused by mutation is made, it can be confirmed by genetic testing. Genetic testing also determines whether family members are carriers, and it can be used to carry out antenatal diagnosis in subsequent pregnancies.

TREATMENT:
The aim of treatment is to prevent infection. In cases of mild immunodeficiency, such as IgG2 deficiency, prophylactic antibiotics may be adequate.

TAQAROB 4/6

 In more severe antibody deficiency, immunoglobulin replacement therapy is required. Antibodies against a wide range of pathogens are needed, and, therefore, Ig pooled from several thousand normal donors is used. Ig replacement can be given intravenously or subcutaneously. Replacement therapy is very different from high-dose Ig replacement therapy, which is immunosuppressive. Plasma donors are screened for HIV and hepatitis B and C antibodies. Multiple steps are usually taken to reduce the risk for hepatitis C carriage-for example, pasteurization (heating to 56C) or adding detergents. None of these steps is guaranteed to remove prions, the agents responsible for "mad cow disease" and variant Creutzfeldt-Jakob disease. If SCID is diagnosed Stem cell transplantation; but until this can be done, simple steps are taken to avoid serious infection. These include avoiding live vaccines (e.g., measles, mumps, rubella, and polio) and using prophylaxis against opportunist infections, such as Pneumocystis carinii pneumonia. Gene Therapy Gene therapy uses recombinant technology to correct the genetic defect in stem cells, which can then reconstitute the immune system. For gene therapy to be successful, several criteria must be met. 1. The genetic mutation for each patient must be identified, and there must be evidence that correcting the mutation will improve his or her conditions. (Insertion of normal genes may not correct a dominant mutation). 2. 3. The inserted gene must be regulated appropriately.

The gene must be delivered to the cell safely. Viral constructs are often used to deliver the normal gene. Healthy humans contain many harmless retroviruses that may recombine genetic sequences with the viral vector. The new viruses produced may be able to cause disease. Gene therapy must not cause malignancy. If a gene with an active promoter is inserted next to an oncogene, the latter may become constitutively active and cause cancer. This is known as insertional mutagenesis, and it remains a major cause for concern. Gene therapy has been used successfully in a handful of patients with -chain deficiency, a type of Xlinked SCID. Stem cells are transfected with the -chain gene and give rise to large numbers of normal daughter cells. 4.

TAQAROB 5/6

 These cells proliferate and replace the abnormal cells because the transfected -chain gene allows
them to proliferate in response to cytokines; these cells have a strong survival advantage.

The normal cytokine gene is transfected at random into anywhere in the genome. There have been two major problems with gene therapy for X-linked SCID.
1. The procedure does not work for older children, perhaps because of loss of thymic function. 2. The normal gene may be inserted next to an oncogene.
BOX: A Delayed Diagnosis:

CVID often develops in the late teens and early twenties. Once immunoglobulin treatment is started, the frequency and severity of respiratory infections diminishes.
BOX: Wiskott-Aldrich Syndrome

lymphoma in patients with immune deficiencies is often caused by the Epstein-Barr virus. Wiskott-Aldrich syndrome is an X-linked disorder, but sometimes it can occurr de novo. Wiskott-Aldrich syndrome protein (WASp) regulates the actin cytoskeleton, and defects in WASp prevent the normal development of platelets. After normal T-cell activation, Zap 70 activates WASp molecules leading to changes in the cytoskeleton, which appear to help in the formation of an immunologic synapse and, in cytotoxic T cells, delivery of perforin and granzyme into target cells. With defects in these T-cell functions, intracellular viral pathogens cannot be cleared in patients with Wiskott-Aldrich syndrome. In addition, these patients have defects in B-cell and dendritic cell function, resulting in impaired antibody production.

Done!

TAQAROB 6/6