Impaired lymphocyte reconstitution after autologous transplant is associated with apoptosis of CD8+ T cells and adverse clinical outcome.

We noticed that the lymphocyte counts, after autologous hematopoietic stem cell transplantation, oscillated during the first 4 post-transplant months. Thereafter, the lymphocyte counts stabilized and segregated the patients into two groups, those who normalized their lymphocyte counts and those with prolonged lymphopenia. In both groups, the CD4 counts remained low for at least 6 months. However, in approximately half of the patient, the CD8 counts increased to normal or above normal values. Patients with prolonged lymphopenia had higher rates of lymphocytes' spontaneous apoptosis and the lymphocytes in patients who restored their counts expressed the intracellular CD14-derived MO2 epitope that protects the cells from apoptosis. These findings were translated to longer disease-free survival and overall survival in patients who restored the CD8 counts. Collectively, our data show that post-transplant lymphocytes that express intracellular CD14-MO2 epitope have survival advantage.

Transglutaminase 6 Antibodies in the Serum of Patients With Amyotrophic Lateral Sclerosis.

IMPORTANCE: Celiac disease is an autoimmune disorder triggered by gluten in genetically predisposed individuals. Gluten sensitivity can cause neurologic manifestations, such as ataxia or neuropathy, with or without gastrointestinal symptoms. Many patients with gluten ataxia produce antibodies toward the newly identified neuronal transglutaminase 6 (TG6). Two case reports described patients initially diagnosed with amyotrophic lateral sclerosis (ALS) and ultimately with celiac disease who improved with a strict gluten-free diet. OBJECTIVE: To evaluate the prevalence of celiac disease-related antibodies and HLA antigen alleles, as well as TG6 antibodies, in patients with ALS and healthy individuals serving as controls to determine whether a neurologic presentation of a gluten-related disorder mimicking ALS might occur in some patients. DESIGN, SETTING, AND PARTICIPANTS: In a case-control study conducted in an ALS tertiary center, we measured serum levels of total IgA antibodies, IgA antibodies to transglutaminase 2 (TG2) and endomysium, as well as IgA and IgG antibodies to deamidated gliadine peptide and TG6 and performed HLA antigen genotyping in 150 consecutive patients with ALS and 115 healthy volunteers of similar age and sex. Participants did not have any known autoimmune or gastroenterologic disorder and were not receiving any immunomodulatory medications. The study was conducted from July 1, 2010, to December 31, 2012. MAIN OUTCOMES AND MEASURES: Antibody levels and frequency of individuals with abnormal antibody values as well as frequency of HLA antigen alleles were compared between patient and control groups. RESULTS: All patients and control group participants were seronegative to IgA antibodies to TG2, endomysium, and deamidated gliadine peptide. Twenty-three patients (15.3%) were seropositive to TG6 IgA antibodies as opposed to only 5 controls (4.3%) (P = .004). The patients seropositive for TG6 showed a classic picture of ALS, similar to that of seronegative patients. Fifty patients and 20 controls were tested for celiac disease-specific HLA antigen alleles; 13 of 22 TG6 IgA seropositive individuals (59.1%) were seropositive for celiac disease-related alleles compared with 8 (28.6%) of the 28 seronegative individuals (P = .04). Mean (SD) levels of IgA antibodies to TG2 were 1.78 (0.73) in patients and 1.58 (0.68) in controls (normal, <10). In a subset of study participants, mean levels of deamidated gliadin peptide autoantibodies were 7.46 (6.92) in patients and 6.08 (3.90) in controls (normal, <16). Mean levels of IgA antibodies to TG6 were 29.3 (30.1) in patients and 21.0 (27.4) in controls (P = .02; normal, <26). CONCLUSIONS AND RELEVANCE: The data from this study indicate that, in certain cases, an ALS syndrome might be associated with autoimmunity and gluten sensitivity. Although the data are preliminary and need replication, gluten sensitivity is potentially treatable; therefore, this diagnostic challenge should not be overlooked.

Hypoparathyroidism and central diabetes insipidus: in search of the link.

UNLABELLED: Two siblings (a 15-year-old boy and an 11-year-old girl) who presented with hypocalcemic seizure at the age of 2 years and 2 months (boy) and 2 years and 4 months (girl) were diagnosed with hypoparathyroidism. At the age of 3 years, the girl developed central diabetes insipidus with good response to desmopressin acetate treatment. The family history was unremarkable, and there was no consanguinity between the parents. The father is of Iraqi/Egyptian Jewish origin and the mother is of Iranian/Romanian Jewish origin. Sequence analysis of the candidate genes for isolated hypoparathyroidism encoding calcium-sensing receptor, parathyroid hormone, and glial cells missing homolog B did not reveal any mutations. Whole-exome sequencing identified a homozygous mutation in the autoimmune regulatory gene (AIRE), c.374A>G;p.Y85C, characteristic for Jewish Iranians with autoimmune polyendocrine syndrome type 1 (APS1), which was confirmed by the Sanger sequencing. Antibodies against the adrenal, pancreatic islet cell, ovary, thyroid, pituitary, celiac, and parietal cell were negative in both siblings, while anti-diuretic hormone antibodies were positive only in the girl. No other symptoms or signs of APS1 developed during all the years of follow-up. CONCLUSION: APS1 should be part of the differential diagnosis in children presenting with isolated hypoparathyroidism or hypoparathyroidism with central diabetes insipidus (CDI). These cases show that the AIRE mutation characteristic of Iranian Jews can also be found in non-Iranian Jews.

Elevated titers of anti-thyroperoxidase antibodies in patients with multiple system atrophy: a pilot study.

OBJECTIVES: Multiple system atrophy (MSA) is a neurodegenerative disease characterized by progressive neuronal loss and alpha-synuclein deposition in oligodendroglial cells in the central nervous system. The cause of MSA remains essentially unknown. A cerebellar syndrome was associated with autoimmune thyroid disease in some cases, apparently not related to MSA and was partially responsive to immunomodulatory therapy. PATIENTS AND METHODS: 28 euthyroid patients who fulfilled the diagnostic criteria for probable MSA, 11 with MSA-cerebellar type (MSA-C), 17 with MSA-parkinsonian type (MSA-P), 28 patients with Parkinson's disease (PD) and 26 normal euthyroid controls were tested the for serum levels of anti-thyroperoxidase antibodies (anti-TPO) and anti-thyroglobulin (Anti-TG) antibodies (Ab). RESULTS: The laboratory results were statistically similar in all three groups, but 3 MSA-C patients had highly elevated anti-TPO Ab titers. CONCLUSION: We identified the presence of elevated anti-TPO levels in a small subgroup of MSA-C patients but neither in MSA-P or PD patients nor in healthy controls. These findings may suggest an autoimmune etiology in some cases of MSA-C.

Overexpression of a novel lymphocyte population, positive for an intracellular CD14-like antigen, in patients positive for human immunodeficiency virus type 1.

CD14, originally recognized as a lipopolysaccharide (LPS) receptor, has recently been implicated in the process of T-cell suppression and apoptosis. Its soluble form has been shown to bind, in vitro, to human T cells, a process that may carry a negative signal onto these cells. We recently described a novel lymphocyte population in human peripheral blood, a population that expresses an intracellular CD14-like antigen. This novel T-cell population, composed mainly of CD8 cells and of very few CD4 cells, was found to be greatly enhanced in asymptomatic, untreated human immunodeficiency virus (HIV)-positive individuals. In the present study, we further characterized this cell population and found that it differed from other CD8 subpopulations associated with HIV infection such as CD8/CD38. In addition, we followed HIV patients under conditions of highly active antiretroviral therapy (HAART) and observed two groups of patients: patients in whom the CD14-like positive-testing T cells returned to normal within 1 to 3 months, and patients in whom it did not, in spite of a significant plasma HIV-RNA viral load decrease. Thus, this new CD14-like positive-testing lymphocyte population may represent an interesting and important component of the cellular events associated with HIV infection. On the basis of its modulation following HAART, we speculate that it may be used, in the future, as a drug-monitoring cellular marker in antiretroviral treatment.

An intracellular antigen that reacts with MO2, a monoclonal antibody to CD14, is expressed by human lymphocytes.

CD14, a lipopolysaccharide (LPS) receptor, is present on the surface membrane of phagocytic leukocytes; it is also present in a soluble form in serum. Recently published results confer to this molecule novel functions that are linked to T-cell activation and to apoptosis. We report here that we have defined and characterized a novel lymphocyte population in human peripheral blood, a population that expresses an intracellular antigen detectable with MO2, a monoclonal antibody directed against the human CD14 molecule. This population is composed primarily of CD8-positive T-cells. We found surprisingly that this novel MO2-positive population of lymphocytes was greatly enhanced in asymptomatic, untreated HIV-positive individuals.