Introduction to severe combined immunodeficiency

Introduction

Due to the congenital differentiation of lymphoid stem cells, the lack of T cells and B cells in the baby after birth, so that both humoral and cellular immunity are defective.Severe combined immunodeficiency(severe combined immunodificiency, SCID) can be divided into X-linked genetic, autosomal recessive and sporadic. It is a heavy one belonging to the combined immunodeficiency disease.

Cause

(1) Causes of the disease

The disease is a polygenic genetic disease. Patients have significant defects in the T cell and B cell systems and are inherited in a concomitant or autosomal recessive manner (eg, Swiss-type gamma-globulinemia). Most patients (95%) are boys, 50% to 60% are sexually inherited, and there are autosomal recessive and scattered cases. In some cases, pluripotent stem cells may not be properly developed into B cells and T cells. The whole body lymphoid tissue is almost completely absent, and it is impossible to synthesize immunoglobulin by itself, and the cellular immune function is almost completely lacking.

(two) pathogenesis

The genetic defect of the hereditary severe combined immunodeficiency disease is the mutation of the γ chain of the interleukin-2 receptor. Several other interleukin receptors also share this γ chain with the interleukin-2 receptor, thus explaining the serious immunodeficiency of this disease. Sex. Early development of T cells requires several interleukin receptors, so if a mutant allele is activated, the female carrier with the mutation undergoes "non-random inactivation" of T cells and cannot survive.

The most common type of autosomal recessive genotype combined with immunodeficiency disease is due to mutations in genes encoded by purine degrading enzymes, adenosine deaminase, and purine nucleoside phosphorylase. The toxicity to lymphocytes comes from the accumulation of purine metabolites. Defects in MHC expression may involve class I or class II MHC molecules, namely HLA-DP, DQ, DR. Class I MHC defects are due to mutations in genes encoding the protein that is transferred to a similar class I MHC molecule, TApl or TAP2.

Defective children with CD8 cells and natural killer cells. The pathogenesis of class II MHC deficiency is complex, and is associated with transactivation factors such as class II transactivation factors on chromosome 15, and defects in RFX5 on chromosome 2. In patients with MHC class II deficiency, CD4 cells are not deficient in CD8 cells, and their T cells are unable to respond to specific antigens. Despite the normal number of B cells, low gamma globulinemia is present in affected children. Patients with this disease may also have defects in lymphocyte activation, including defects in CD3 T cell receptors, cytokines such as interleukin-2 production or signaling such as ZAP-70 deficiency.

symptom

The child develops within 1 to 2 months after birth. It is resistant to bacterial, fungal, viral and protozoal infections, and various infections continue. Infants often develop skin, lung and gastrointestinal infections. Almost all children have diarrhea. The stool culture is seen in Salmonella or pathogenic Escherichia coli. Persistent skin and mucosal Candida infections can occur even before broad-spectrum antibiotics are applied. The incidence of delirium is increased and can be generalized.

The child is also not resistant to a virus with a weak pathogenicity. Herpes, rubella or varicella virus infection is very serious, and the measles course and rash last longer. Give some patients vaccination orBCGProgressive bovine rash or systemic tuberculosis may occur. There are always sinus and respiratory infections during the course of the disease. Pseudomonas aeruginosa lung abscess and pneumocystic pneumonia are common causes of death. Often accompanied by children with growth and development disorders.

diagnosis

1. Immunological examination B and T cell functions were significantly inhibited in vivo and in vitro. Generally, the number of lymphocytes did not change much, and lymphocytes decreased significantly in severe cases. After 6 months of birth, the serum immunoglobulin is often lower than O.25g/L, and the peripheral blood lymphocyte count is often lower than 1.5×109/L, and there is no immune function. No gamma-globulinemia is more common, but in some cases the immunoglobulin value can be normal or increased. The response to antigenic stimuli is poor, so the inflammatory response seen in infected tissues is very light.

2. Prenatal examination For families born to affected children, prenatal testing of the disease may be performed by classifying fetal blood fluorescence activated cells with monoclonal antibodies or by analyzing enzyme levels in cultured amniotic cells.

3. Carriers detect the mother of a boy with a sexually-typed gland The boy can be detected by selective inactivation of an abnormal X chromosome in T cells and B cells.

Histopathological examination: The thymus is small in size, less than 1.0 g, composed of dysplastic epithelial cells and interstitial cells, lacking thymus bodies and lymphocytes. Peripheral lymphoid germinal centers and follicles are absent, often without plasma cells.

complication

There are always sinus and respiratory infections during the course of the disease. Pseudomonas aeruginosa lung abscess and pneumocystic pneumonia are common causes of death.

treatment

Western medicine treatment

General therapy

(1) Strengthening care and nutrition: to improve the patient's resistance and immunity.

(2) Prevention of infection: attention should be paid to isolation to minimize contact with pathogens. For severe combined immunodeficiency disease, the child must be placed in a sterile warehouse for a long time until the immune function is reestablished.

(3) Avoid vaccination: For newborns suspected of having immunodeficiency, live vaccination such as vaccinia and BCG should be banned in order to avoid systemic vaccinia caused by vaccination against vaccinia, and systemic dissemination caused by vaccination with BCG. Measles and polio vaccines should also be avoided.

Anti-infective therapy is low in cellular immunity and humoral immunity. The body cannot kill infected viruses, bacteria, fungi and other pathogens. Therefore, once an infection occurs, broad-spectrum antibiotics, effective antiviral agents and antifungal drugs should be selected for treatment. Since bacteriostatic antibiotics do not prevent the spread of pathogenic bacteria, bactericidal antibiotics should also be used for treatment.

Immunotherapy

(1) Substitute for humoral immune deficiency:

1 human serum γ-globulin: mainly using γ-globulin for replacement or compensation therapy. Patients with congenital gamma-globulinemia die more than 10 years of age. If appropriate replacement therapy such as treatment with human serum gamma-globulin is given, the child can survive normally and even live to adulthood. The dose is 100-200 mg/kg each time, intramuscularly, once a month. Serum immunoglobulin concentrations of 3.0 g / L can help control infection. Since the half-life of γ-globulin is 0.5 to 1 month, it can be maintained at a dose of 2.0 g/L by intramuscular injection at a dose of 100 mg/kg. Long-term repeated injections may cause local scar formation, occasionally shock-like reactions such as fever, rash, urticaria, asthma and blood pressure drop, and should be treated according to anaphylactic shock in time.

2 normal human plasma: normal human plasma infusion also has the effect of replacing γ-globulin preparation, the dose is 10ml/kg each time, every 3 to 4 weeks. However, for patients with severe combined immunodeficiency disease, preparations containing immunocompetent cells, such as whole blood and white blood cell-containing plasma, should not be infused to avoid GVHR.

3 human gamma globulin: can also be infused monthly human gamma globulin 600ml / kg to improve serum immunoglobulin levels.

(2) Substitute for cellular immunodeficiency: mainly to supplement T lymphocytes and enhance T cell function.

1 Infusion of fresh whole blood: The risk of severe GVHR caused by differences in tissue matching needs to be considered before transfusion. Therefore, before the blood infusion, it is necessary to irradiate 25 to 50 Gy (2500 to 5000 Rad) radiation to eliminate the proliferation ability of T cells, prevent lymphocytes in the blood from entering the neonatal body and attack the host tissues, thereby avoiding the occurrence of severe GVHR. However, repeated blood transfusions are still prone to allergic reactions.

2 transfer factor (TF): a lymphokine released by T lymphocytes, which can transfer normal human-specific immune information to T cells, activate the resting lymphocytes, and thereby restore and expand the cellular immune response. It works rapidly, and the negative skin test can receive a positive reaction after 18 to 24 hours after receiving the corresponding transfer factor, and it can last for several months. It can be used clinically in immunodeficiency diseases with eczema and thrombocytopenia. It can exert a certain degree of immune reconstitution and can control the infection of viruses, fungi or some intracellular bacteria. A dose of 2 ml (equivalent to an extract of 1.8 × 108 white blood cells), intramuscular injection, once a day or every other day, for 3 to 6 days. The injection site is preferably a subcutaneous tissue close to the lymph nodes.

3Thymosin(thymosin): a peptide hormone extracted from bovine thymus or porcine thymus, which not only induces T cell differentiation and development, but also enhances the response of mature T cells to antigen or other stimuli, enhances immune function, and regulates immune balance. It can be used for immunodeficiency diseases and severe combined immunodeficiency diseases with eczema and thrombocytopenia, but only to improve clinical symptoms. Dosage 5 ~ 10mg, intramuscular injection, once a day, once every 1-3 weeks, changed to the next day or once a week for several months.

4 interferon (IFN): is a lymphokine produced when cells infect the virus, can inhibit the proliferation of the virus and promote the activation of natural killer (NK) cells, so it can enhance the antiviral ability of patients with immune dysfunction. A commonly used preparation is γ-interferon prepared from human blood leukocytes. The dose is 1 million U, intramuscular injection, once every other day or twice a week for several months. Genetically engineered recombinant interferon makes the drug source more abundant.

5Aldileukin (interleukin-2): A lymphokine produced by T helper cells that promotes the proliferation of lymphocytes and other immune-active cells and enhances the ability of NK cells and lymphokines to activate killer cells. Experiments with neonatal animal viral infections have shown that the drug has a protective effect on the host.

6Adenosine deaminase (ADA)In patients with severe combined immunodeficiency disease, some are related to the lack of ADA, while normal human red blood cells contain a large amount of ADA. Therefore, infusion of fresh red blood cells after replacement and irradiation can temporarily correct the immunodeficiency caused by ADA deficiency. Intramuscular injection of high-dose bovine ADA-conjugated polyethylene glycol (PEG-ADA) once a week also has a good effect. It is also believed that a large number of purine degrading enzymes in red blood cells can degrade toxic products such as deoxy ATP in lymphocytes of patients.

7 bone marrow transplantation: through the allogeneic bone marrow transplantation, the patient is implanted with normal hematopoietic stem cells, which can reconstruct normal cellular and humoral immune functions, which is the preferred treatment for patients with this disease. According to reports, the cure rate for severe combined immunodeficiency disease is up to 50%, which is also an ideal treatment for immunodeficiency patients with eczema and thrombocytopenia.

The ideal donor is the same egg twins, because the twins can have the same congenital defects, so it is not suitable for congenital immunodeficiency disease. Donors with identical HLA in siblings can also be used. In the case of bone marrow transplantation for congenital immunodeficiency disease, different degrees of immunosuppressive preparation should be selected according to the degree of cellular immunodeficiency to prevent rejection of the transplanted bone marrow. When implanting >0.5×108/kg bone marrow nucleated cells in patients with severe combined immunodeficiency disease, immunosuppressive preparation can be completely eliminated, but the degree of cellular immunodeficiency is less complete, such as immunodeficiency disease with eczema and thrombocytopenia. Patients are required to apply strong immunosuppressive preparations, such as high doses of cyclophosphamide and busulfan (Maliland). Or systemic radiation to avoid rejection.

For the prevention of GVHR after bone marrow transplantation, cyclosporine can be used to selectively inhibit immunocompetent cells. During the transplantation process and for a period of time, some protozoa such as Pneumocystis carinii, a virus such as herpes virus, are infected due to low immune function. It can be controlled by using sulfamethoxazole/trimethoprim (complex sulfamethoxazole) and high titer-specific anti-herpesvirus immunoglobulin.

8 fetal liver transplantation: The fetal liver of the gestational age from 2 to 6 months contains a large number of hematopoietic stem cells, including lymphocyte stem cells, so fetal liver transplantation can replace some of its effects before there is no suitable bone marrow transplant donor. Generally, the fetal liver of 3 to 5 months gestational age is used, and the fetus is induced by the water sac. One or more fetal livers can be used for one treatment, and the number of cells to be implanted must be 3.0×108/kg or more. Clinically applied to severe combined immunodeficiency disease.

9 Thymus transplantation: Thymosin secreted by thymus corpuscle plays an important role in the maturation of T cells. Therefore, the thymus of the fetus can be implanted into the patient in various ways to promote the maturation of T cells and restore cellular immune function. Thymus transplantation can be performed in a variety of ways: the homogenate or slice of the fetal thymus can be implanted into the rectus abdominis muscle; or the thymic epithelial cells can be implanted in vitro; implanted with the thymus gland containing blood vessels, and The blood supply blood vessels are anastomosed to the small blood vessels in the abdominal cavity of the patient. Thymus transplantation is also suitable for patients with severe combined immunodeficiency disease, which can improve part of immune function

prevention

1. Strengthen care and nutrition to improve patient resistance and immunity.

2. Prevention of infection should pay attention to isolation and minimize contact with pathogens. For severe combined immunodeficiency disease, the child must be placed in a sterile warehouse for a long time until the immune function is reestablished.

3. Avoid vaccination For newborns with suspected immunodeficiency, live vaccination such as vaccinia and BCG should be banned in order to avoid systemic vaccinia caused by vaccination against vaccinia, and systemic dissemination caused by vaccination with BCG. Measles and polio vaccines should also be avoided.