Correspondence

Pure Red-Cell Aplasia

N Engl J Med 1999; 340:2004-2005June 24, 1999

Article

To the Editor:

Handgretinger et al. (Jan. 28 issue)1 present evidence that a clone of large granular lymphocytes induced pure red-cell aplasia by attacking erythroid progenitors with a deficiency of HLA class I antigens. They show that glycophorin A+ erythroblasts normally express low levels of HLA class I antigens and that they are lysed by the clonal cells.

But the authors provide almost no data that can explain why granulocytes are unaffected in the disease. They made no attempt to lyse myeloblasts in vitro or to measure the expression of HLA class I antigens as a function of a myeloid maturation-specific antigen. Furthermore, since HLA class I antigens are lost slowly during erythropoiesis,2 the mechanism they propose would most likely affect the later stages more than the earlier stages of erythropoiesis and cause ineffective erythropoiesis and intravascular hemolysis of mature red cells rather than red-cell aplasia.

From studies of a very similar patient,3 we concluded that T cells specifically suppressed erythropoiesis from progenitors and found major-histocompatibility-complex–dependent suppression of erythropoiesis in the rather limited in vitro culture systems used at that time. These results contradict those of Handgretinger et al., but perhaps the clonal population of γ/δ T cells in their patient had a unique interaction with erythroid cells.

David G. Nathan, M.D.
Colin A. Sieff, M.B., B.Ch.
Dana–Farber Cancer Institute, Boston, MA 02115

3 References

1
Handgretinger R, Geiselhart A, Moris A, et al. Pure red-cell aplasia associated with clonal expansion of granular lymphocytes expressing killer-cell inhibitory receptors. N Engl J Med 1999;340:278-284
Full Text | Web of Science | Medline

2
Robinson J, Sieff C, Delia D, Edwards PA, Greaves M. Expression of cell-surface HLA-DR, HLA-ABC and glycophorin during erythroid differentiation. Nature 1981;289:68-71
CrossRef | Web of Science | Medline

3
Lipton JM, Nadler LM, Cannelos GP, Kudisch M, Reiss CS, Nathan DG. Evidence for genetic restriction in the suppression of erythropoiesis by a unique subset of T lymphocytes in man. J Clin Invest 1983;72:694-706
CrossRef | Web of Science | Medline

To the Editor:

Handgretinger et al. describe a case of pure red-cell aplasia resulting from the destruction of erythroblasts by large granular γ/δ T lymphocytes. The mechanism in this case appears to hinge on the physiologic down-regulation of HLA class I molecules in the erythroid lineage. In the accompanying editorial, Raulet1 concludes that these findings are evidence of autoimmunity against cells with a low level of expression of HLA antigens. Similar manifestations may occur in patients with congenital deficiency of HLA class I antigens, in which these molecules are deficient in all nucleated cells. One of the first patients to be described with this disease had aplastic anemia,2 which many consider to be an autoimmune disease. In most patients, the deficiency results from a mutation in the peptide transporter, which reduces surface expression of HLA class I antigens by over 95 percent. Natural killer cells from these patients have no cytotoxic activity against autologous cells unless they are stimulated with interleukin-2.3

Chronic bacterial infections and inflammation of the respiratory tract (sinusitis or bronchiectasis) are the main clinical features of congenital deficiency of class I HLA antigens. Inflammatory cytokines may thus activate natural killer cells, which would kill infected as well as surrounding intact cells, contributing to the progressive degradation of airway tissues.3 Vasculitis, which sometimes affects these patients, may also result from damage to autologous endothelial cells.4

Jacques Zimmer, M.D.
Dagmar Regele, M.D.
Henri de la Salle, Ph.D.
Etablissement de Transfusion Sanguine, F-67065 Strasbourg CEDEX, France

4 References

1
Raulet DH. Does a low level of expression of HLA molecules engender autoimmunity? N Engl J Med 1999;340:314-315
Full Text | Web of Science | Medline

2
Payne R, Brodsky FM, Peterlin BM, Young LM. “Bare lymphocytes“ without immunodeficiency. Hum Immunol 1983;6:219-227
CrossRef | Web of Science | Medline

3
Zimmer J, Donato L, Hanau D, et al. Inefficient protection of human TAP-deficient fibroblasts from autologous NK cell-mediated lysis by cytokines inducing HLA class I expression. Eur J Immunol (in press).

4
de la Salle H, Zimmer J, Fricker D, et al. HLA class I deficiencies due to mutations in subunit 1 of the peptide transporter TAP1. J Clin Invest 1999;103:R9-R13
CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Even if the clinical presentation of our patient was similar to that of the patient referred to by Nathan and Sieff, 1 the mechanism involved may be rather different. T cells from their patient did not mediate unrestricted cytotoxicity or display allospecific and lectin-dependent cytolysis. In contrast, freshly isolated γ/δ T lymphocytes from our patient were cytotoxic to killer-cell–sensitive K562 cells and killer-cell–resistant Daudi cells. However, the T cells from the other patient1 had been cryopreserved before analysis in vitro and may have lost their cytolytic capacity after thawing.

Suppression of erythropoiesis by the cells from the patient referred to by Nathan and Sieff appeared to be major-histocompatibility-complex–restricted.1 The cells from our patient, however, expressed the γ/δ T-cell receptor that in most cases does not recognize antigens presented by HLA self-antigens. Indeed, these γ/δ killer T cells were inhibited from lysis by HLA class I self-antigens because they expressed various class I inhibitory receptors. They preferentially lysed target cells that had lost HLA class I antigens or that expressed low levels of HLA class I molecules, such as erythroid progenitors.

The lack of involvement of myeloid cells in the disease can be explained by the fact that myeloid cells express normal levels of HLA class I antigens, which protect them from lysis. To our knowledge, myeloid cells do not have diminished expression of HLA class I antigens, and the data in Figure 3 of our article are compatible with this view. As we mentioned in our report, allogeneic myeloid cells expanded ex vivo were resistant to lysis by the patient's killer cells, whereas ex vivo–expanded allogeneic erythroid cells were sensitive to lysis. Furthermore, lymphocytes from our patient did not suppress erythropoiesis in colony assays, in contrast to the findings in the patient referred to by Nathan and Sieff.1

It is conceivable that in other patients, natural effector cells might express unusual combinations of inhibitory or activating HLA class I receptors that damage autologous HLA class I–positive tissues. Such T cells may not be sufficiently inhibited by the HLA class I self-antigens expressed by these tissues, or the T cells may carry aberrant activating receptors for HLA self-antigens. Autoimmune disease might be induced after in vivo activation of such killer cells by nonspecific stimuli, in a manner similar to the mechanism observed by Zimmer et al. in vitro with natural killer cells from patients with congenital deficiencies of HLA class I antigens.

Rupert Handgretinger, M.D.
University of Tübingen, D-72076 Tübingen, Germany

Paul Fisch, M.D.
University of Freiburg, D-79104 Freiburg, Germany

1 References

1
Lipton JM, Nadler LM, Cannelos GP, Kudisch M, Reiss CS, Nathan DG. Evidence for genetic restriction in the suppression of erythropoiesis by a unique subset of T lymphocytes in man. J Clin Invest 1983;72:694-706
CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1
Roger Grau, Karl S Lang, Dorothee Wernet, Peter Lang, Dietrich Niethammer, Carsten M Pusch, Rupert Handgretinger. (2004) Cytotoxic activity of natural killer cells lacking killer-inhibitory receptors for self-HLA class I molecules against autologous hematopoietic stem cells in healthy individuals. Experimental and Molecular Pathology 76:2, 90-98
CrossRef