levoleucovorin and Immunologic-Deficiency-Syndromes

A high incidence of severe B-cell immunodeficiency and chronic reactivated Epstein-Barr virus (EBV) infection in patients with chronic fatigue syndrome (CFS) is reported herein. Of the 58 patients evaluated, 100% had evidence of prior EBV exposure and 72% had evidence for reactivated EBV infection. Notably, 94% of CFS patients had B-cell immunodeficiency with a marked depletion of their CD19+IgM+ mature B-lymphocyte population. A remarkable 81% of CFS patients experienced subjective improvement of their symptoms after treatment with folinic acid (CAS 58-05-9, leucovorin). The findings provide unprecedented evidence that CFS frequently is a folinic acid responsive clinical entity accompanied by B-cell immunodeficiency and inappropriate antibody responses to EBV.

Topics: Adult; Antibodies, Viral; Antigens, Viral; B-Lymphocytes; Biomarkers; Capsid; Epstein-Barr Virus Infections; Fatigue Syndrome, Chronic; Female; Flow Cytometry; Humans; Immunologic Deficiency Syndromes; Leucovorin; Male; Middle Aged; Pain; Phenotype; Recurrence

Insufficient dietary folate intake, hereditary malabsorption, or defects in folate transport may lead to combined immunodeficiency (CID). Although loss of function mutations in the major intestinal folate transporter PCFT/SLC46A1 was shown to be associated with CID, the evidence for pathogenic variants of RFC/SLC19A1 resulting in immunodeficiency was lacking. We report two cousins carrying a homozygous pathogenic variant c.1042 G > A, resulting in p.G348R substitution who showed symptoms of immunodeficiency associated with defects of folate transport. SLC19A1 expression by peripheral blood mononuclear cells (PBMC) was quantified by real-time qPCR and immunostaining. T cell proliferation, methotrexate resistance, NK cell cytotoxicity, Treg cells and cytokine production by T cells were examined by flow cytometric assays. Patients were treated with and benefited from folinic acid. Studies revealed normal NK cell cytotoxicity, Treg cell counts, and naive-memory T cell percentages. Although SLC19A1 mRNA and protein expression were unaltered, remarkably, mitogen induced-T cell proliferation was significantly reduced at suboptimal folic acid and supraoptimal folinic acid concentrations. In addition, patients' PBMCs were resistant to methotrexate-induced apoptosis supporting a functionally defective SLC19A1. This study presents the second pathogenic SLC19A1 variant in the literature, providing the first experimental evidence that functionally defective variants of SLC19A1 may present with symptoms of immunodeficiency.

Topics: Folic Acid; Humans; Immunologic Deficiency Syndromes; Leucovorin; Leukocytes, Mononuclear; Methotrexate; Proton-Coupled Folate Transporter; Reduced Folate Carrier Protein

Topics: Antifungal Agents; Drug Combinations; Glucuronates; Humans; Immunologic Deficiency Syndromes; Infant; Infusions, Intravenous; Leucovorin; Male; Pentamidine; Pneumonia, Pneumocystis; Quinazolines; Respiratory Insufficiency; Trimethoprim, Sulfamethoxazole Drug Combination; Trimetrexate

Interference with any organ system during development leads to permanent damage. Severe disease or starvation during the first four months of extrauterine life lead to a persistent deficiency of cell mediated immunity, which changes the life expectancy and later disease patterns in population groups. Severe intercurrent disease, starvation or trauma later in life lower cell mediated immunity only temporarily.

Topics: Allergy and Immunology; Animals; Child Development; Female; Fetal Diseases; Humans; Immunity, Cellular; Immunologic Deficiency Syndromes; Infant; Infant, Newborn; Leucovorin; Male; Mice; Morbidity; Nutrition Disorders; Pregnancy; Starvation; Thymus Gland