GENERAL INFORMATION
• T and B cells are defective together.
• The mildest form is Wiskott-Aldrich syndrome, the most severe form is seen in severe combined immunodeficiency.
• It occurs due to a defect in one of the necessary steps (cytokines, cytokine receptors) for the immune response to occur.
Treatment
• In patients with primary T cell defects or combined T and B cell defects, MHC-matched sibling or haploidentical (semi-matched) parental stem cell transplantation is the most appropriate treatment option.
SEVERE COMBINED IMMUNE DEFICIENCIES (SCID)
ADA deficiency
Purine nucleoside phosphorylase (PNP) deficiency
Omenn Syndrome
Reticular dysgenesis
• Adenylate kinase 2 defect.
• Severe neutropenia and deafness are seen with classical SCID findings.
Diagnosis
Signs of B cell failure
- Absence of plasma cells in the bone marrow
- Absence of superficial lymphoid tissue
- Lymph nodes, tonsils, adenoids and Peyer's plaques are hypoplasic or absent.
- Immunoglobulin levels are markedly decreased or absent.
Signs of T cell failure
- Generally, there is significant lymphopenia (<1500/mm3).
T cell rosette is decreased.
No thymus shadow on chest film
There are no lymphocytes in the follicular and paracortical areas of the spleen.
All tests showing T cell functions are defective.
Skin tests are negative (PPD negative).
No specific antibody response occurs after vaccination.
Diagnosis is made by demonstrating that the peripheral numbers and functions of T and B lymphocytes are decreased in patients.
In the X-linked form, T lymphocytes and NK cells were decreased and B cells were increased. NK and B cell functions are decreased.
In ADA deficiency (OR), all lymphocyte types are markedly reduced. There is severe lymphopenia (<500/mm3). The number of NK cells is decreased and their functions are normal.
TREC (T-cell Receptor Excision Circle) test is an effective and safe screening test in severe Combined Immunodeficiency (SCID). It is based on the measurement of residual DNA fragments formed during the gene recombination stage during the development of T lymphocytes. Thus, it is possible to obtain information about T lymphocyte production in the thymus.
Treatment
Pneumocystis carinii and Candida infections are treated appropriately. Blood products should be irradiated to avoid viable T cells. The best treatment is stem cell transplantation. Fetal liver or fetal thymus transplantation can also be performed.
Radiosensitive immunodeficiencies
• Ataxia-Telangetasia
• Artemis defect
• DNA ligase 4 deficiency
ATAXY TELENGY KTAZI
• It shows autosomal recessive inheritance.
• Both B and T cell functions are impaired. It is associated with neurological disorders.
• The first finding, cerebellar ataxia 9-12. It occurs in months (may be delayed up to 4-6 years of age).
• Telangiectasia appears before 2 years of age (it can be delayed up to 8-9 years). Telangiectasias first start from the bul bar conjunctiva, then appear in the auricle, on the nose, and in the antecubital region.
• In time, choreoathetoid movements, extrapyramidal neurological symptoms also occur and mental retardation is common.
• Seborrheic dermatitis, oculocutaneous telangiectasias, atopic dermatitis, vitiligo and hyperpigmentation are seen on the skin.
• There are recurrent sinopulmonary infections.
• Increased risk of lymphoreticular malignancy.
• There is thymus hypoplasia (the sail-shaped shadow of the thymus is not visible on the X-ray).
• There are endocrine disorders such as insulin resistant diabetes, hypogonadism.
Diagnosis
• There are various degrees of disorder in the T and B cell systems. T helper/T suppressor ratio decreased. Cytotoxic T cells are decreased.
• IgG is normal. 50-70% of IgA deficiency is seen. Half of those with IgA deficiency have IgG2 deficiency. IgE is low. He has lymphopenia.
• Serum alpha fetoprotein level increased. Liver functions are impaired.
• Cytotoxic antibodies against the brain and thymus are detected in some of the patients.
• There may be chromosomal abnormalities (such as 7-14 translocations)
• The majority of patients may have antibodies to EBV.
• Radiation-induced chromosome breaks in cell cultures are diagnostic.
Treatment
• Prophylaxis and antioxidant vitamin E is used against infections.
WISCOTT-ALDRICH SYNDROME
• Eczema + recurrent pyogenic infections + thrombocytopenia (small platelets) coexist.
• These patients are deficient in the O-glycosylated leukocyte sialoglycoprotein CD43, which should normally be on the cell surface.
• Shows X-linked transition. Bleeding due to thrombocytopenia begins in the early period. If there is thrombocytopenia in the newborn, it should definitely be considered.
• Often the first sign is bloody diarrhea. Recurrent otitis media, pneumonia, and infections such as meningitis are seen. The disease is progressive. Eczema occurs later (usually around 1 year of age). The tendency to infections is increasing.
• It is especially prone to polysaccharide-containing organism (pneumococcal, meningococcal, H. influenza) infections.
• There is a tendency to chronic renal diseases.
• The frequency of lymphoreticular malignancy increases.
Diagnosis
• He has thrombocytopenia, anemia, Coombs test (+).
• IgG is normal, IgM is decreased, IgA and IgE are increased. B cell counts are normal.
• Antibody response to polysaccharide antigens is insufficient.
• T-cell immunity is initially normal, deteriorates over time.
Treatment
• Antibiotics are given for infections. Immunity is provided passively with IVIG once a month. Bone marrow transplantation can be done.
JOB SYNDROME (HIPER-IGE SYNDROME)
• It is a natural immunity defect: There are OD and OR forms.
Autosomal Dominant Hyper lgE syndrome (Job syndrome)
• It participates in an autosomal dominant manner. It shows variable clinic depending on the defect in one gene (STAT3).
• T, B and NK cell counts are normal. Memory T cell (TH17) counts are decreased.
• Clinical manifestations result from impaired transmission in type 1 IFN, IL-6, IL-10, IL-22 and EGF receptor signaling pathways.
• It is characterized by severe recurrent staphylococcal abscesses in the skin, joints, lung (pneumatoceles and cysts) and other organs, pneumatoceles in the lung, osteopenia and recurrent bone fractures with delayed teething and minor trauma. The second frequency is C. albicans infections.
• Patients have normal intracellular phagocytosis, metabolism, killing and complement activity.
• Staphylococci have impaired opsonization.
• Serum IgE (>2000 mg/dl) and IgD levels are markedly increased and there is severe eosinophilia (60-70%) in the peripheral smear.
• IgG, A and M are usually normal.
• Itchy pustular dermatoses are seen in newborns and infants.
• Allergic respiratory symptoms are usually NONE
• Rough facial appearance is typical.
Treatment
• The best treatment in the long term is antibiotic therapy against penicillin-resistant staphylococci.
• IVIG
Autosomal Recessive Hyper lgE syndrome
• In autosomal recessive hyper IgE syndrome, which is most frequently observed in Turkey, mutations in the DOCKS gene, which is responsible for T cell activation and proliferation, have been detected.
• Unlike the OD form, viral infections (HPV, HSV, VZV, molluscum) and neurological problems are common.
• Most patients have high serum IgE levels and low IgM levels.
• T cell numbers and functions are decreased. Immunological phenotypes are similar to combined immunodeficiency.
• The differences between autosomal recessive hyper IgE syndrome and Job syndrome are shown in the table.
Interferon receptor gamma 1-2 and interleukin-12 receptor beta-1 mutations
• It is a natural immunity defect.
• Disseminated BCG infection is the typical presentation.
• There is also a predisposition to intracellular microorganisms, especially Salmonella, Listeria and Histoplasma.
NOTE: The same clinical findings are seen in STAT1 mutation.
Other innate immunity defects:
• Pneumonia, meningitis, and sepsis due to S. pneumoniae and S. aureus are seen in IRAK4 (IL-1R-related kinase) and Myd 88 (myeloid differentiation factor) deficiencies. The frequency of clostridium infection has also increased.
• The frequency of Herpes and Human Papilloma Virus (HPV) infections increased in natural killer (NK) deficiencies.
IMMUNE DYSREGULATION AND IMMUNE DEFICIENCY DISEASES
1. Autoimmune lymphoproliferative syndrome: It occurs as a result of mutations in Fas, Fasl or caspase 10 genes. CD3+ T cells lack CD4 and CD8 co-receptors on their surface. As a result, these T cells do not respond to antigens or mitogens (apoptosis disorder). It is characterized by an increase in CD4 and CD8 negative (double negative) T cells in the peripheral blood.
2. APECED (Autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia) syndrome: there is autoimmune regulator protein (AIRE) gene defect. This protein is a transcription factor that provides ectopic expression of self-antigens in the thymus. As a result of this mutation, tolerance to many antigens is impaired and autoimmune diseases occur.
Classic findings;
• Chronic mucocutaneous candidiasis
• Adrenal insufficiency
• Hypoparathyroidism
• Autoimmune diseases: IDDM, thyroiditis, ovarian failure, hepatitis, hypergonodotropic hypogonadism
3. IPEX (Due to Immundysregulation-Polyendocrinopathy-X). There is a FOXP3 mutation.
4. CD25 deficiency
