Does serum gastric parietal cell antibody titer have influence on anemia and vitamin B12 deficiency in atrophic glossitis patients?

BACKGROUND/PURPOSE: Our previous study found 284 gastric parietal cell antibody (GPCA)-positive atrophic glossitis (AG) patients (so-called GPCA+AG patients in this study) in a group of 1064 AG patients. This study evaluated whether high-titer (GPCA titer ≥ 160) GPCA+AG patients had greater frequencies of anemia, vitamin B12 deficiency, macrocytosis, and hyperhomocysteinemia than low-titer (GPCA titer < 160) GPCA+AG patients. METHODS: Complete blood count, serum iron, vitamin B12, folic acid, homocysteine, and GPCA levels in 117 high-titer GPCA+AG patients, 167 low-titer GPCA+AG patients, and 532 healthy control subjects were measured and compared. RESULTS: We found that 12.0%, 29.1%, 23.1%, 16.2%, 1.7%, and 23.1% of 117 high-titer GPCA+AG patients and 5.4%, 17.4%, 17.4%, 7.2%, 1.2%, and 14.4% of 167 low-titer GPCA+AG patients were diagnosed as having macrocytosis, blood hemoglobin, iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia, respectively. Moreover, both 117 high-titer and 167 low-titer GPCA+AG patients had significantly greater frequencies of macrocytosis, blood hemoglobin, serum iron and vitamin B12 deficiencies, and hyperhomocysteinemia than 532 healthy control subjects (all P-values < 0.05). In addition, 117 high-titer GPCA+AG patients also had greater frequencies of anemia (P = 0.029, statistically significant), serum vitamin B12 deficiency (P = 0.027, statistically significant), macrocytosis (P = 0.075, marginal significance), and hyperhomocysteinemia (P = 0.085, marginal significance) than 167 low-titer GPCA+AG patients. CONCLUSION: For GPCA+AG patients, high-titer GPCA+AG patients have greater frequencies of anemia, serum vitamin B12 deficiency, macrocytosis, and hyperhomocysteinemia than low-titer GPCA+AG patients.

Hematinic deficiencies, hyperhomocysteinemia, and gastric parietal cell antibody positivity in atrophic glossitis patients with macrocytosis.

BACKGROUND/PURPOSE: Macrocytosis is defined as having the mean corpuscular volume (MCV) â‰§ 100 fL. This study evaluated whether 41 atrophic glossitis (AG) patients with macrocytosis had significantly higher frequencies of anemia, hematinic deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody (GPCA) positivity than 532 healthy control subjects or 1064 AG patients. METHODS: Complete blood count, serum iron, vitamin B12, folic acid, homocysteine, and GPCA levels in 41 AG patients with macrocytosis, 1064 AG patients, and 532 healthy control subjects were measured and compared. RESULTS: We found that 73.2%, 22.0%, 73.2%, 4.9%, 80.5%, and 56.1% of 41 AG patients with macrocytosis were diagnosed as having blood hemoglobin, iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity, respectively. Moreover, 41 AG patients with macrocytosis had significantly higher frequencies of blood hemoglobin and serum vitamin B12 deficiencies, hyperhomocysteinemia, and serum GPCA positivity than 532 healthy control subjects or 1064 AG patients (all P-values < 0.001). In addition, 41 AG patients with macrocytosis also had significantly higher frequencies of serum iron and folic acid deficiencies than 532 healthy control subjects (both P-values < 0.001). Pernicious anemia was found in 22 AG patients with macrocytosis. CONCLUSION: There are significantly higher frequencies of anemia and serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity in AG patients with macrocytosis than in healthy control subjects. AG patients with macrocytosis also have significantly higher frequencies of blood hemoglobin and serum vitamin B12 deficiencies, hyperhomocysteinemia, and serum GPCA positivity than AG patients.

Selective expansion of regulatory T cells during lenalidomide treatment of myelodysplastic syndrome with isolated deletion 5q.

Lenalidomide (LEN) leads to erythroid improvement in the majority of patients with myelodysplastic syndrome and isolated deletion of the long arm of chromosome 5 (MDS-del(5q)). This effect is believed to be exerted via its immunomodulatory properties, although the precise nature is still incompletely understood. We prospectively performed immune profiling in the bone marrow and blood of MDS-del(5q) patients undergoing LEN therapy for a median of 6 cycles. Therapy with LEN led to a significant increase in the median absolute lymphocyte count (1.3-fold, p = 0.013) without changes in the distribution of the T helper cells within the entire compartment. In parallel, the frequency of Treg increased significantly during treatment both in the peripheral blood (5.0 vs. 9.6 %, p = 0.001) and bone marrow (3.4 vs. 8.1 %, p = 0.001). Surprisingly, LEN treatment led to a decrease in TGFbeta levels, both in the peripheral blood (4.9 vs. 2.3 ng/ml, p = 0.039) and bone marrow (4.5 vs. 0.8 ng/ml, p = 0.023). These changes were not associated with an increase in pro-inflammatory Th17 cells. Taken together, our results demonstrate that LEN induces a shift in lymphocytic populations towards immunosuppression in MDS-del(5q) patients.

Biological activity of lenalidomide in myelodysplastic syndromes with del5q: results of gene expression profiling from a multicenter phase II study.

In vitro studies suggest that haploinsufficiency is involved in the pathogenesis of myelodysplastic syndromes (MDS). In patients with del5q cytogenetic abnormality, RPS-14 and microRNAs (miRNAs) play a major role. In a multicenter phase II single-arm trial with lenalidomide in anemic primary del5q MDS patients with low- or int-1 risk IPSS, biological changes from baseline were investigated. Gene expression profiling of selected genes was performed (TaqMan® Low Density Array Fluidic card, Applied Biosystems PRISM® 7900HT) and normalized against the expression of the 18S housekeeping gene from a pool of healthy subjects. Thirty-two patients were evaluated at baseline and after 3 and 6 months of treatment. RPS-14, miR-145, and miR-146 were downregulated at baseline and significantly increased during treatment. Nuclear factor kappa B, IL-6, interferon regulatory factor-1, IFNγ-R2, IL-2, and many genes in the apoptotic pathways (TNF, IL-1B, and IL-10) were upregulated at baseline and significantly downregulated during lenalidomide treatment, while forkhead box P3, FAS, IFNγ, IL-12A, and IL-12B were downregulated at baseline and progressively upregulated during treatment. The crucial role of aberrant immunological pathways and haploinsufficiency in the pathogenesis of del5q MDS is confirmed in the present patient setting. Our results indicate that lenalidomide may act through defined immunological pathways in this condition.

Erythrocyte chimerism after injection of spleen cells into anemic mice of the W-series.

Anemic mice (W(v)W(v)) when injected at birth with a mixture of isologous (genotype W(v)w) and homologous spleen cells, showed an improvement in their peripheral blood picture when adult. Red blood counts, red cell size, and electrophoresis of the hemoglobins indicated that, in some cases, the homologous tissue had become implanted and, in others, the isologous tissue was functioning.

Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome.

RPS14, CSNK1A1, and miR-145 are universally co-deleted in the 5q- syndrome, but mouse models of each gene deficiency recapitulate only a subset of the composite clinical features. We analyzed the combinatorial effect of haploinsufficiency for Rps14, Csnk1a1, and miRNA-145, using mice with genetically engineered, conditional heterozygous inactivation of Rps14 and Csnk1a1 and stable knockdown of miR-145/miR-146a. Combined Rps14/Csnk1a1/miR-145/146a deficiency recapitulated the cardinal features of the 5q- syndrome, including (1) more severe anemia with faster kinetics than Rps14 haploinsufficiency alone and (2) pathognomonic megakaryocyte morphology. Macrophages, regulatory cells of erythropoiesis and the innate immune response, were significantly increased in Rps14/Csnk1a1/miR-145/146a deficient mice as well as in 5q- syndrome patient bone marrows and showed activation of the innate immune response, reflected by increased expression of S100A8, and decreased phagocytic function. We demonstrate that Rps14/Csnk1a1/miR-145 and miR-146a deficient macrophages alter the microenvironment and induce S100A8 expression in the mesenchymal stem cell niche. The increased S100A8 expression in the mesenchymal niche was confirmed in 5q- syndrome patients. These data indicate that intrinsic defects of the 5q- syndrome hematopoietic stem cell directly alter the surrounding microenvironment, which in turn affects hematopoiesis as an extrinsic mechanism.

Hematological findings and antibody responses in Syrian hamster (Mesocricetus auratus) infected with Babesia microti.

Hematological findings during the course of infection and the antibody response in Syrian hamsters infected with Babesia microti were examined. A macrocytic hypochromic anemia with an increase of the reticulocyte count was detected as a rise in the parasitized erythrocyte rate. White blood cell counts also remarkedly increased with the increases of both neutrophils and active-shaped monocytes, and thus they particularly play an important role in eliminating the parasite. In Western blotting with the sera from the hamsters infected with B. microti, a 38 kDa protozoan antigen reacted to the early-term sera, and additionally 28, 32, and 34 kDa antigens also reacted to the medium- and latter-term, and convalescent sera. These antigens were immunodominant and the antibodies against these antigens had also important roles for inhibition of this parasite.

Depressed cell-mediated immunity in megaloblastic anemia due to folic acid deficiency.

Cell-mediated immunity has been studied in patients with 1) megaloblastic anemia of folic acid deficiency, 2)megaloblastic anemia of pregnancy, or 3) iron-deficiency anemia. Using dinitrochlorobenzene skin tests, phytohemagglutinin-stimulated lymphocyte transformation, and rosette inhibition by antilymphocyte globulin, we have shown that cell-mediated immunity is depressed in megaloblastic anemia due to folate deficiency; this depression was reversed by folate treatment. Cell-mediated immunity was not impaired by iron-deficiency anemia. Suggested interactions between iron deficiency and folate metabolism were not clarified by these studies.

Isolated anaemia as a manifestation of Rh isoimmunisation.

Rh isoimmunisation leads to haemolytic anaemia and hyperbilirubinaemia in the first h of life. Isolated early onset neonatal anaemia has rarely been reported. The authors describe the case of a term infant, born to an 'A' negative, second gravida mother. On the second day of life, pallor was noticed. His haemoglobin (Hb) was 6.8 g/dl, he had reticulocytosis and a positive direct antiglobulin test. However, he did not have a high total serum bilirubin (TSB) (87.2 µmol/l). He was transfused with red blood cells and kept under phototherapy for 3 days. Three weeks later, he received another transfusion for severe anaemia (Hb 6 5 g/dl). During this period, he was never jaundiced and the maximum level of TSB was 122 µmol/l. On follow-up, his Hb stabilised and he had no further problems. This report highlights the possibility of early onset anaemia without jaundice as the sole manifestation of Rh isoimmunisation.

Asynchronous expression of granulocyte membrane receptors in megaloblastic anaemia.

The expression of Fc(IgG) and C3b membrane receptors by granulocytes and their precursors was examined in 23 cases of megaloblastic anaemia which were graded I-III according to morphological severity. Fractionated bone marrow and peripheral blood granulocyte receptors were assessed by rosette formation with optimally sensitized ox erythrocytes and the results compared with those found in 14 normal marrows. Promyelocyte Fc and C3b receptor activities in megaloblastic anaemia did not differ from normal whilst the number of Fc receptor positive myelocytes and later cells showed a significant increase (P less than 0.05 in Grade I, P less than 0.01 in Grades II and III) proportional to the severity of megaloblastosis. An increase in the number of C3b receptor positive granulocytes was seen in early megaloblastic anaemias and, in contrast to Fc receptor expression, showed the highest receptor activities in the Grade II cases. The most significant changes in receptor expression were seen at the metamyelocyte stage and appear to be related to the numbers of these cells found in the megaloblastic marrows. It is suggested that these alterations are primarily related to asynchronous granulocyte maturation and the application of these findings to the study of granulocytic disorders is discussed.

Experimental production of possible autoimmune castritis followed by macrocytic anemia in athymic nude mice.

A specific gastritis was induced in BALC/c (+/?) mice by thymectomy within 3 days after birth (25 to 45 per cent) or in BALB/c (nu/nu) mice by the injection of spleen cells (10(7)) from neonatally thymectomized mice (70 per cent). Normal peripheral lymphoid cells, irrespective of the sex and dose, were generally ineffective in inducing gastritis in nude mice, while thymus cells were partially effective (30 per cent). The induced gastritis was characterized by a loss of chief and parietal cells and by varying degrees of lymphoid cell infiltration along thickened muscularis mucosa. The fundic mucosa was replaced by mucous necklike immature cells, and there was a rise of pH of the gastric juice. Argyrophilic endocrine cells escaped the inflammation and increased in number. The gastritis induced in nude mice was generally more severe and was often followed by severe macrocytic anemia. Megaloblast-like large immature erythroid cells were numerous in the spleens of affected mice. Antiparietal cell antibodies (IgG) were always demonstrated by an indirect immunofluorescence test in the sera of gastritis-developing mice, but were absent in sera of normal or untreated conventional nude mice. These findings suggest a new animal model of pernicious anemia in man.

Colony-forming ability of bone marrow cells of W anaemic mice on macrophage layer formed in peritoneal cavity of mice.

The colony-forming ability of haematopoietic cells of W anaemic mice was examined on the macrophage layer formed in the peritoneal cavity of mice. Bone marrow cells of W anaemic mice formed a considerable number of colonies on the macrophage layer, notwithstanding they did not form any colonies in the spleen of the same recipients. As the colony-forming ability of the bone marrow cells was not reduced by the incubation with 3-H-thymidine, most of the cells which formed colonies on the macrophage layer seemed to stay in G0 state. The interrelationship between the spleen colony-forming cells, the macrophage-layer colony-forming cells, and in vitro colony-forming cells was discussed.

Humoral and cellular immunity to intrinsic factor in myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease often associated with other autoimmune disorders. A case history of MG with a coexisting atypical megaloblastic anaemia with vitamin B12 deficiency and anti Intrinsic Factor (IF) antibodies, led to a study of humoral and cellular immunity to IF in 81 MG patients. Within this series, 3 other patients had a disturbed humoral and cellular immunity to IF. These 3 patients presented no other features of pernicious anaemia. The possible origins and significance of the anti IF antibodies in MG patients are discussed.

Reversible C3 hypocomplementaemia in megaloblastic anaemia due to vitamin B12 deficiency.

Serum C3 and C4 levels have been determined in patients with Addisonian pernicious anaemia (PA) and megaloblastic anaemia due to vitamin B12 deficiency from other causes, before and after treatment, in order to study the interaction between vitamin B12 deficiency and complement and the role of complement in the pathogenesis of the gastric lesion of PA. C3 levels are significantly reduced in vitamin B12 deficiency and return to normal on treatment; C3 levels correlate with the degree of anaemia but not with serum vitamin B12 levels at diagnosis. C4 levels are normal. These observations suggest that the observed C3 hypocomplementaemia is not a consequence of immune mechanisms, but may be due to altered synthesis of C3 complement component.

Lymphocyte subpopulations in megaloblastic anaemia due to vitamin B-12 deficiency.

Lymphocyte subpopulations were measured in the blood of 17 patients with megaloblastic anaemia due to vitamin B-12 deficiency. 14 patients had pernicious anaemia and 3 others were gastrectomized. By using monoclonal antibodies recognizing T cell surface markers and immunofluorescence microscopy, we found a significant decrease in the number of circulating suppressor T cells and an increase in the ratio of helper to suppressor T lymphocytes in pernicious anaemia patients. This finding may be related to other immune abnormalities found in pernicious anaemia, e.g. the presence of multiple autoantibodies.