IMMUNOLOGY TEXTBOOK - Mercury Podillia 2013

CONGENITAL IMMUNE DEFICIENCY

Combined T- and B-Cell Immunodeficiencies

Prevalence: 10–25% of all Primary immunodeficiencies.

Class="center">Severe Combined Immunodeficiency (SCID)

X-linked form

Specific defect: Impaired stem Cell Differentiation into B AND T lymphocytes. A defect in the common gamma chain of the IL-2 receptor on T lymphocytes. The gamma chain acts as a signal transducer upon receptor binding to IL-2.

Autosomal recessive form.

Specific defect: Mutation in the ZAP-70 Tyrosine kinase Gene, which serves as a signal transducer in T lymphocytes essential for their proliferation. Characterized by the absence of CD8+ Cells in the peripheral Blood.

Chromosomal localization of the defect: Xq 13-21.1.

Clinical Features. Recurrent infections, weight loss, developmental delay. Characteristic lymphopenia and thymic hypoplasia. Reduced T-lymphocyte count and function. Hypogammaglobulinemia, decreased B-lymphocyte levels. Impaired Skin tests and antibody production. Patients typically die within the first 1–2 years of life from viral, bacterial, or protozoal infections, or mycoses.

Treatment. Bone Marrow transplantation, antibiotic therapy, intravenous immunoglobulin therapy, fetal Liver and Thymus cell transplantation.

Ataxia-Telangiectasia (Louis-Bar Syndrome)

(ICD-10 code G11.3),

Autosomal Recessive Inheritance pattern

Specific defect. Impaired T- and B-lymphocyte function. Decreased levels of IgA, IgE, and IgG. Hypoplasia of the thymus, Spleen, Lymph Nodes, and Tonsils. Extremely high levels of alpha-fetoprotein detected in the serum.

Chromosomal localization of the defect: 11q22.3 (ATM).

Clinical features. Cutaneous and ocular telangiectasias; progressive cerebellar ataxia; recurrent viral and bacterial infections of the Paranasal Sinuses and Lungs; Bronchiectasis; elevated alpha-fetoprotein levels. Long-term outlook includes damage to the nervous, endocrine, and vascular systems, as well as malignancies. The disease is most commonly diagnosed at 5–7 years of age with equal frequency in boys and girls. Half of the patients exhibit intellectual disability, adynamia, and a narrow range of interests. Some patients survive up to 20 or even 40 years of age (Tables 50, 51).

Treatment. Symptomatic care. Bone marrow transplantation. Thymic Hormones. Intravenous immunoglobulin therapy.

As an example of the Immune Response in combined immunodeficiency, we present the case history of patient Zh., a 9-year-old girl suffering from ataxia-telangiectasia (Louis-Bar syndrome), who was evaluated at the City Pediatric Immunology Center (Table 55).

From early childhood, the patient frequently suffered from bacterial infections (Pneumonia, Chronic Bronchitis, sinusitis), viral infections (frequent acute respiratory viral infections occurring more than 3 times a year, chronic recurrent herpes affecting the Lips and facial skin), intestinal dysbiosis, and candidiasis of the esophageal, laryngeal, tracheal, and intestinal mucosa. Since the age of 5, she exhibited ataxia and experienced recurrent epistaxis due to telangiectasias in the Nasal cavity. At 9 years of age, the patient developed a Sarcoma of the left knee joint, which led to her death. The patient was diagnosed with hereditary combined T- and B-cell immunodeficiency: ataxia-telangiectasia (Louis-Bar syndrome).

Immunogram of patient Zh., 9 years old: revealed a profound suppression of T- and B-cell Immunity (combined immunodeficiency), specifically cytotoxic CD8+ T cells, CD16+ natural killers, and CD19+ B lymphocytes; reduced production of IgG and IgA; neutrophilic leukocytosis with a tendency toward decreased phagocytic activity.

Treatment:

1) Zadaxin (thymosin alpha-1) subcutaneously (s.c.), 1.2 mL (1 vial = 1.6 mg, therapeutic dose = 900 mcg/m2) twice a week, with 3–4 day intervals between injections, course duration 6–12 months.

2) Laferon (laferobion) intramuscularly (i.m.), 2 million IU 3 times a week, for 4–6 weeks.

3) famciclovir 0.25 g orally 2 times a day for 8–12 months; Herpovir (ointment) applied to the affected areas of the skin and labial mucosa 4 times a day for 7 days during an acute flare-up;

Immunorehabilitation:

4) immunofan 0.005% 1 ml subcutaneously twice a week, course of 15 injections.

5) cyclferon - interferon inducer - 12.5% injection solution - 2 ml, single dose 0.25 g intramuscularly on days 1, 2, 4, 6, 8, 11, 14, 17, 20, 23, 26, 29. Prescribed after Interferon Therapy.

Table 55. Immunogram of female patient Zh., aged 9

Wiskott-Aldrich syndrome (WAS, X-linked immunodeficiency)

(ICD-10 code D82.0)

WAS is an X-linked primary immunodeficiency disorder characterized by a triad of symptoms manifested in boys from early childhood: 1) increased susceptibility to infections (frequent acute respiratory infections, bronchopulmonary infections, ENT infections, skin, mucosal, Urinary Tract, and gastrointestinal infections); 2) hemorrhagic syndrome caused by thrombocytopenia; 3) atopic dermatitis and eczema.

Specific defect. Impaired activation of CD4+ and CD8+ cells. Defective production of IgM against encapsulated Bacteria (pneumococci). IgG levels are normal. IgA and IgE levels are elevated. Isohemagglutinins are reduced or absent. The number of B lymphocytes is generally normal.

Chromosomal localization of the defect: Xp11.23-11.3 of the X chromosome.

Clinical features. Initial manifestations may appear from 2 to 5 months of age, presenting the classic triad: eczema, thrombocytopenia, and frequent pyogenic infections. Over time, autoimmune disorders, malignancies, and hemorrhagic syndrome (melena, purpura, epistaxis) develop. Condition stabilization is possible with age (Table 51).

Immunological findings: decreased levels of hemoglobin, erythrocytes, and platelets; elevated eosinophil levels; altered serum immunoglobulin levels (low IgM, normal IgG, high IgA, very high IgE). T-cell parameters in WAS are variable, and their interpretation can be challenging (Table 50).

Treatment. Bone marrow transplantation. In patients prone to bleeding, splenectomy is recommended to reduce hemorrhagic manifestations, along with supportive therapy and immunomodulators targeting T- and B-cell immunity.

Correction of anemia: replacement therapy with packed red Blood Cells when Hb drops <50 g/L. Intensive blood Transfusion Therapy is indicated for massive hemorrhages. To prevent a potential graft-versus-host disease reaction in patients with profound T-cell deficiency, transfusion blood must be pre-irradiated at a dose of 300 rad.

Atopic dermatitis is treated with steroid ointments and creams (hydrocortisone, Advantan, Elocon, etc.).

The condition of children with WAS is unstable; therefore, an optimal inpatient and outpatient management regimen must be established. Whenever possible, the patient should be isolated in a separate room during hospitalization due to the risk of contact with respiratory viral and nosocomial flora. For the same reasons, attendance at children's groups or schools is contraindicated for patients with WAS. Vaccination with live viral Vaccines and polysaccharide antigen-containing products should be avoided.

Nijmegen breakage syndrome

Nijmegen breakage syndrome is a form of combined immunodeficiency endemic to Ukraine. It is characterized by an autosomal recessive inheritance pattern caused by a mutation in a gene located on chromosome 8. Impaired DNA Repair leads to the accumulation of DNA damage. Children with Nijmegen breakage syndrome are frequently of Slavic descent.

Clinical presentation: progressive microcephaly with age. Brain abnormalities: subarachnoid cysts, agenesis of the corpus callosum, Hydrocephalus; "bird-like" facies featuring a sloping forehead, prominent cheekbones, a large Nose, and relatively large, dysplastic ears. Growth retardation, delayed Puberty, and oligophrenia. Pigmentation anomalies in the form of "café-au-lait" spots. Occasionally telangiectasias, pigmented nevi, capillary or cavernous hemangiomas. Premature graying. Developmental anomalies of other systems. Recurrent respiratory infections leading to bronchiectasis. Cause of death includes malignancies: lymphomas, acute lymphoblastic leukemia, Hodgkin's lymphoma.

Immunological findings: lymphopenia, predominantly affecting CD4+ lymphocytes; inversion of the CD4+/CD8+ ratio; elevated NK cell counts; IgA deficiency; IgG subclass deficiency leading to hypogammaglobulinemia; normal or even elevated IgM levels.

Treatment: stem cell transplantation.

X-linked Hyper-IgM Syndrome

(ICD-10 code D81.0)

X-linked immunodeficiency with CD40 Ligand abnormality and hyper-IgM is a combined primary immunodeficiency disorder.

Specific defect. Absence of the CD40 ligand on T-helper cells. The interaction between T AND B lymphocytes through CD40 ligand–CD40 molecular contact is a critical event required for B-cell isotype switching from IgM synthesis to The production of other immunoglobulin classes and The formation of a plasma cell clone of corresponding Specificity. Low levels of IgG, IgA, and IgE.

Chromosomal localization: Xq 26.27. X-linked form.

Clinical features. Affects boys. Characterized by recurrent bacterial infections and an increased incidence of opportunistic infections, notably those caused by Pneumocystis carinii (Tables 50, 51).

Treatment. Replacement therapy. Antibacterial agents. Administration of soluble CD40 ligand.

Immunodeficiency with dwarfism is characterized by intestinal malabsorption syndrome and recurrent infectious diseases.

Good's syndrome

Good's syndrome is a severe combined immunodeficiency associated with thymoma. The mode of inheritance has not been established.

Histologically—delayed thymus development.

Clinical presentation: recurrent bacterial, viral, and fungal infections; predisposition to malignancies.

Immunological findings: reduced T cells, pre-B cells, and IMMUNOGLOBULINS; eosinopenia.

Myelogram: erythroblastopenia, aplastic anemia.

McKusick metaphyseal chondrodysplasia (short-limbed dwarfism syndrome, Cartilage-Hair hypoplasia syndrome)

Immunodeficiency associated with short-limbed dwarfism syndrome is characterized by an autosomal recessive mode of inheritance.

Clinical features: disproportionate body proportions from birth, short and thick limbs, short stature, prominent skin folds around the neck and limbs, small and abnormally shaped Teeth, flattening of vertebral bodies, lumbar lordosis, flattened chest, outward flaring of the lower Ribs, lower limb deformity, joint hypermobility accompanied by an increased range of motion, and hair growth defects.

Intestinal malabsorption syndrome, celiac disease, recurrent infections.

Immunological findings: lymphopenia, T lymphocytes with low functional activity, decreased B-cell and immunoglobulin levels, and normal NK cell counts.

Treatment: immunomodulators and Antibiotics.