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14 Other Important Primary
In addition to the major primary immunodeficiencies described in other chapters, there are other less common, but wel -described, immunodeficiencies. These less common disorders can be classified into four categories: Less common antibody deficiencies Less common cel ular deficiencies Less common phagocytic cel deficiencies Less common innate immune defects Other Important Primary Immunodeficiency Diseases Less Common Antibody Deficiencies
Similar to the patients described in the chapters Selective IgE Deficiency on X-linked Agammaglobulinemia (XLA), Hyper IgM Syndrome, Selective IgA Deficiency, Common IgE is the allergy antibody. It is typically very low Variable Immunodeficiency, IgG Subclass (< 5 IU/ml) in up to 10 percent of the patients Deficiency and Specific Antibody Deficiency, attending an allergy clinic. Most of the patients individuals with less common antibody deficiencies are not ill, but recurrent respiratory infections have usually present with upper respiratory infections been described in some patients.
or infections of the sinuses or lungs. Laboratory studies show low immunoglobulins and/or Immunodeficiency with deficient antibody function. The patients often Thymoma (Good's Syndrome) improve with antibiotics but get sick again when these are discontinued. These illnesses include the This primary immunodeficiency is associated following disorders: with a benign thymic tumor. Good's Syndrome is usually first suspected when a thymic tumor Autosomal Recessive is seen on a chest X-ray. Most patients are adults. Removal of the thymic tumor does not cure the immunodeficiency although it may help These patients resemble patients with XLA including other symptoms.
a profound deficiency of immune globulins, antibodies and B-cel s, but their BTK gene, the Antibody Deficiency with gene defective in XLA, is normal. Several dif erent Transcobalamin II Deficiency genetic abnormalities have been described. Each of these abnormalities is inherited as an autosomal Transcobalamin 2 is a protein that transports recessive trait (see chapter titled Inheritance). vitamin B12 to the tissues from the gastrointestinal Therefore, both males and females can be af ected tract. A hereditary deficiency is associated with with these deficiencies. These patients should be anemia, failure to thrive, low white cell counts and treated with immunoglobulin replacement therapy.
hypogammaglobulinemia. It can be treated with B12 injections.
Antibody Deficiency with Normal or Elevated Warts, Hypogammaglobulinemia, Infection, Myelokathexis These patients have severe infections similar to patients with Common Variable Immunodeficiency, WHIM is an autosomal recessive disorder (see but their immunoglobulin levels are normal or chapter titled Inheritance) with severe warts, elevated. They have decreased antibody levels recurrent bacterial and viral infections and low, to most vaccine antigens, both protein and but not absent, immunoglobulins and neutropenia polysaccharide, which differentiate them from (low granulocytes). The latter is due to failure of selective antibody deficiency patients.
the bone marrow to release granulocytes into the blood stream (myelokathexis). WHIM is caused by a Selective IgM Deficiency defective gene for CXCR4, a chemokine protein that regulates leukocyte movement. Treatment includes These patients have low IgM (less than 30 mg/dl immunoglobulin replacement therapy and G-CSF in adults, less than 20 mg/dl in children) with (see chapter titled Specific Medical Therapy).
recurrent infections that are often severe. There are variable antibody responses. Some patients are asymptomatic. This disease may fit into the group of disorders called Common Variable Immunodeficiencies.
Other Important Primary Immunodeficiency Diseases Less Common Primary Cellular Immunodeficencies
Drug-Induced Antibody One hereditary form of CMC is the APECED Syndrome (autosomal recessive polyendocrinopathy-candidiasis-ectodermal Several pharmaceuticals may depress dysplasia) associated with multiple endocrine immunoglobulin and antibody levels, and this problems (eg hypothyroidism or Addison disease) may result in recurrent infections. The chief due to an AIRE gene defect on chromosome 21. drugs implicated include high-dose steroid A few CMC patients develop severe hepatitis drugs (particularly when given intravenously), or bronchiectasis. Treatment requires life-long anticonvulscent drugs (Dilantin and others), anti-inflammatory drugs used for arthritis, and the monoclonal antibody, Rituximab (Rituxan). Cartilage Hair Hypoplasia (CHH) The latter drug targets B-cells, the precursor of the antibody-producing plasma cells. CHH is an autosomal recessive immunodeficiency In rare instances, severe and permanent associated with dwarfism. It is particularly hypogammaglobulinemia can occur with drug common among the Amish because of family therapy, but usually the hypogammaglobulinemia intermarriage. Most patients have very fine reverses when the drug is discontinued.
brittle hair and an unusual susceptibility to viral infections. The immunodeficiency is variable Cellular immunodeficiencies discussed in and usually involves both antibody and cellular previous chapters included severe combined immunity. Some patients have been treated by immunodeficiency, ataxia telangiectasia, bone marrow transplantation, but this will not Wiskott-Aldrich syndrome and the DiGeorge correct their hereditary short stature.
syndrome. Some patients with less common cellular immunodeficiencies also have severe X-linked Lymphoproliferative immunodeficiency with early onset and significant morbidity and mortality while others have mild problems. All have some defect of their T-cell XLP is characterized by life-long vulnerability to (cellular) immune system, recognized by Epstein-Barr virus (EBV) infection, which can lead deep-seated infections, viral and fungal infections, to severe and fatal infectious mononucleosis, and tuberculosis and other mycobacterial lymph node cancers (lymphomas), combined infections. Most of the other, less common T-cell immunodeficiency and, less commonly, aplastic deficiencies described below are relatively rare.
anemia or vasculitis. XLP is associated with a defect on the X chromosome termed SH2DIA. Chronic Mucocutaneous This defect affects males. The mothers of the Candidiasis (CMC) affected males and possibly some of their sisters are carriers (see chapter titled Inheritance). CMC is characterized by persistent Candida (fungus) infections of the mucous membranes, scalp, skin Most XLP patients do well until they are exposed and nails, but not of the blood stream or internal to EBV. Then, they become seriously ill with fever, organs (i.e. not systemic candidiasis). CMC is usual y swollen lymph nodes, enlarged liver and spleen, congenital and often hereditary, with onset in infancy and hepatitis. If they recover, they go on to manifested by persistent oral Candida infections develop one of the above-named problems. Some (thrush). Later, the nails and skin become chronical y patients are misdiagnosed with common variable infected. These infections respond to anti-Candida immunodeficiency. Early recognition is crucial treatment but recur when the treatment stops.
since the disease can be cured by bone marrow or cord blood transplantation. Immunoglobulin CMC is associated with a selective T-cell replacement therapy is often used, but this will not deficiency to Candida and a few related fungi, but prevent the EBV infection.
otherwise their immune system is fine. The most common abnormal laboratory test is a negative delayed hypersensitivity skin test to Candida antigen despite widespread Candida infection. Other Important Primary Immunodeficiency Diseases Less Common Primary Cellular Immunodeficencies continued
spleen. The illness results from a genetic inability X-linked Immune Dysregulation to make interferon and/or IL-12, two proteins that with Polyendocrinopathy (IPEX) are especially important in helping to kill these bacteria within the white blood cel s. Several genetic forms and several dif erent molecular pathways are IPEX is characterized by multiple autoimmune responsible. Treatment includes antibiotics and bone endocrine diseases (particularly diabetes and thyroid problems), chronic diarrhea and a rash resembling eczema. IPEX is associated with abnormalities of a gene on the X chromosome Natural Killer Cell Deficiency termed FOXP3. These boys have activated T-cells This is a rare disorder characterized by recurrent which stimulate autoimmune problems. Early herpes virus infection and a selective deficiency immunosuppressive medications (cyclosporin or of natural killer (NK) cells. Natural killer cells are tacrolimus) followed by bone marrow transplantion lymphocytes (about 10 percent of the circulating are commonly used as treatments.
lymphocytes) that are neither T- nor B-cells. Natural killer cells kill tumors and viral-infected Interferon-g/IL-12 Pathway cells and represent an early defense against cancer and viral infection. These patients may have recurrent or chronic herpes infections such These deficiencies are genetic disorders as cold sores, severe Epstein-Barr virus infection, characterized by a special susceptibility to or varicella (chickenpox). Many of the patients mycobacteria (the family of bacteria which cause require continuous anti-viral medicines.
tuberculosis and related infections) and salmonella infections. Many of the infants become ill as a result of a live BCG tuberculosis vaccination, given routinely at birth in many countries (not USA). Other patients have skin infections, swol en lymph nodes or blood stream infections with an enlarged liver and Less Common Phagocytic Cell Deficiencies
The chief phagocytic white blood cell is the Neutropenia can occur at birth and can be polymorphonuclear granulocyte (also known as life-long. One form, termed severe congenital neutrophil). To be effective, the neutrophil must neutropenia (Kostmann syndrome), is an move to a site of infection, ingest the organism autosomal recessive disorder. This disorder is and then kill the organism (see chapter titled associated with a gene abnormality of G-CSFR or The Immune System and Primary the receptor for G-CSF, a cytokine that stimulates granulocyte growth. These infants require G-CSF and may have bone marrow transplantation. Another form of neutropenia is cyclic neutropenia which is an autosomal dominant disorder in which Neutropenias are disorders characterized by low the neutropenia occurs every 2 to 4 weeks and numbers of granulocytes, usually defined as a lasts about a week. It is associated with a gene neutrophil count of less than 500 cells/ul (normal is defect termed ELA-2. more than 2000 cells/ul). Depending on its severity and duration, neutropenia can lead to serious and A third form, benign chronic neutropenia, has fatal infection or intermittent infection of the skin, low but not life-threatening neutropenia and is mucus membranes, bones, lymph nodes, liver, often asymptomatic. Treatment for all of these spleen or blood stream (sepsis).
disorders may include antibiotics for infections, prophylactic antibiotics, G-CSF injections and bone marrow transplantation.
Other Important Primary Immunodeficiency Diseases Less Common Phagocytic Cell Deficiencies continued
Several primary immunodeficiencies have an Specific Granule Deficiency associated neutropenia. These immunodeficiecies include X-linked hyper-IgM syndrome, X-linked Specific granule deficiency is associated with agammaglobulinemia, and WHIM syndrome. killing defects and decreased granules within their Some of these patients acquire an autoimmune antibody to their own neutrophils. This antibody causes neutropenia due to accelerated destruction Glycogen Storage Disease of the neutrophils.
Phagocyte Killing Defects Glycogen storage disease type Ib is a disorder Several rare phagocyte defects have an inability with neutropenia, poor granulocyte killing, a large to kill organisms similar to patients with chronic liver and low blood sugar. It is due to a defect of granulomatous disease (CGD) (see chapter the enzyme glucose-6 phosphate transporter 1 titled Chronic Granulomatous Disease). They with accumulation of glycogen in the liver.
should be suspected in patients who seem to have CGD but tests for that disorder are normal. b-actin Deficiency These include enzyme defects or deficiencies of glucose-6-phosphate dehydrogenase, b-actin Deficiency is associated with poor myeloperoxidase, glutathione reductase and granulocyte movement (chemotaxis) and glutathione synthetase. recurrent infection. b-actin is a structural protein that allows cell movement. Some patients with chemotactic disorders have severe periodontitis and early tooth loss. Three of these syndromes are termed Papillon-Lefebre syndrome, prepubertail periodontitis, and juvenile periodontitis. Less Common Innate Immune Defects
Innate immunity includes those body defenses that associated with a defect of a gene termed NEMO are present at birth and do not increase following which encodes an enzyme (IKK-g) necessary microbial exposure or immunization. for nuclear signaling (see chapter titled Hyper IgM Syndrome). Many of these latter patients Toll-like Receptor (TLRs) have defects of sweating, sparse hair, abnormal dentition, and an antibody deficiency.
Toll-like receptors are proteins present on the Mannose-binding Lectin (MBL) surface of many leukocytes that react with proteins present on many microbes. Upon contact with an organism these TLRs send internal messages to MLB is a deficiency of a circulating protein that the nucleus of the cell to secrete cytokines, which allows microbes to activate the complement stimulate the immune system, and kill invading system. A hereditary deficiency of MBL is associated with recurrent severe infections. A partial deficiency may aggravate other Several immunodeficiencies have been recently problems such as cystic fibrosis, HIV or lupus described in which cellular proteins that should transmit the message from the TLRs to the nucleus are abnormal, resulting in failure of cytokines to be produced in response to bacterial infection. One of these is a disorder termed IRAK-4 deficiency. Another is ectodermal dysplasia with immunodeficiency (EDA-ID), an X-linked disorder

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