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We describe a unique case of a patient with a three-year history of idiopathic CD4(+) T cell lymphopenia (HIV negative) who presented with stage IV diffuse large cell non Hodgkin's lymphoma with t(8;22). Despite the severe lymphopenia, the patient tolerated intensive chemotherapy well and at 18 months, remains in complete remission.
The peripheral lymphocyte pool size is governed by homeostatic mechanisms. Thus, grafted T cells expand and replenish T cell compartments in lymphopenic hosts. Lymphopenia-driven proliferation of naive CD8+ T cells depends on self-peptide/MHC class I complexes and the cytokine IL-7. Lymphopenia-driven proliferation and maintenance of memory CD8+ T cells are MHC independent, but are believed to require IL-7 and contact with a bone marrow-derived cell that presents the cytokine IL-15 by virtue of its high affinity receptor (IL-15Ralpha). In this study we show that optimal spontaneous proliferation of grafted naive and memory CD8+ T cells in mice rendered lymphopenic through gene ablation or irradiation requires the presence of CD11chigh dendritic cells. Our results suggest a dual role of CD11chigh dendritic cells as unique APC and cytokine-presenting cells.
Lymphocyte subpopulation studies in 21 patients with Sjögren's syndrome and rheumatoid arthritis revealed an absolute lymphopenia and a normal percentage of T- and SIg-cells. In one patient, a large percentage of lymphocytes bore both IgG and IgM; after cell trypsinization only IgM was resynthesized. This surface IgM was capable of binding human IgG, suggesting that the presence of multiple classes of immunoglobulins on the surface of these lymphocytes was due to surface rheumatoid factor activity. Profound lymphopenia was associated with high concentrations of cryoglobulins and the presence of lymphocytotoxic antibodies. These antibodies were broadly reactive, causing cytotoxicity of T- and SIg-cells from normal subjects, from viral and lymphoproliferative disease subjects, from different organs, and SIg-cells from human lymphoblastoid cell lines. Lymphocyte transformation after phytohemagglutinin and pokeweed mitogen stimulation was impaired in comparison to normal subjects. Warm washing of the lymphocytes and purification to greater than 80 per cent T-cells did not restore mitogen responsiveness to normal, suggesting that cell coating by an antibody and diminished responder cell number were inadequate explanations for the impaired transformation.
Lymphopenia was induced in mice by a single injection of cyclophosphamide. IL-7 or a control protein were administered to the mice twice daily and the cellularity and composition of the spleen, lymph node, bone marrow, and thymus were determined at various time points thereafter. In comparison to the control cyclophosphamide-treated mice, animals receiving cyclophosphamide and IL-7 had an accelerated regeneration of splenic and lymph node cellularity. There was no significant difference in the rate of recovery of the bone marrow and thymus of the control and IL-7-treated mice. Assessment of the pre-B cell compartment revealed a dramatic increase in total pre-B cell numbers in the spleen and bone marrow of the IL-7-treated mice as measured by both flow microfluorimetry and a pre-B cell colony-forming assay. This was followed in a few days by a significant increase in surface IgM+B cell numbers to levels above normal values in both the spleen and lymph node. IL-7 administration to cyclophosphamide-treated mice also resulted in an accelerated recovery of peripheral CD4+ and CD8+ cell numbers in the spleen and lymph node. The numbers of CD8+ cells were increased by twofold over normal levels in cyclophosphamide-treated mice receiving IL-7. Myeloid recovery was determined in cyclophosphamide treated mice by assessing the numbers of CFU-granulocyte-macrophage and Mac 1+ cells. There was no significant difference in myeloid recovery between cyclophosphamide-treated mice receiving IL-7 or control protein. These results suggest that administration of IL-7 after chemical-induced lymphopenia may have therapeutic benefits in shortening the period required to achieve normal lymphoid cellularity.
The numbers of cells bearing the T3 (pan-T cell), the T4 (putative helper/inducer cells), the T8 (putative suppressor/cytotoxic cells) and B cell phenotypic markers were counted in venous blood samples from 26 newly diagnosed pulmonary tuberculosis patients and 29 healthy controls from East Java. The absolute T cell count was lower in the patients and T4 cells were fewer in patients (mean 748/mm3) than in controls (mean 1,043/mm3), but there were no significant differences in total T8 cell and B cell counts between patients and controls. The T4:T8 ratio was not disturbed in many patients, but it was less than 1.6 in 11 of 26 patients and in only three of 29 controls: this ratio was less than 1.2 (the lower limit of 'normal') in six patients but no controls. The intensity of the T4 lymphopenia was unrelated to the extent of the lesion seen radiologically or the size of the skin test reaction to PPD. Levels of interferon-alpha were not elevated in the serum of any of the patients or controls. It is suggested that the T4 lymphopenia was a reaction to the mycobacterial infection and not a manifestation of underlying secondary (acquired) immune deficiency.
Since BOTTGER (1966, 1969) AND HOFFBRAND (1968) had described the absolute lymphopenia in pulmonary sarcoidosis as a sign of immune deficiency there were several authors who tried to elucidate different problems of sarcoidosis (RACOVEANU et al. 1970, STOJAN et al. 1971, OSODA et al. 1972). One of these problems is the effort to correlate absolute lymphopenia to prognostic parameters. Three controlled therapeutic trials were performed and compared: 59 cases with clinically and histologically proven sarcoidosis with spontaneous regression and 180 cases with different regimens of prednisolone: --a steady increase of the absolute number of lymphocytes in cases without and with treatment is a prognostically good sign, --no increase or even decrease is a poor sign, -- a very low and unchanged number is worst. This seems to confirm--among other things--that course and prognosis of sarcoidosis really may not be affected by time-limited corticotherapy.
Although mild peripheral eosinophilia is a common finding in Sjögren's syndrome (SS), severe eosinophilia with a clinical picture simulating hypereosinophilic syndrome is extremely rare. We report a 24 year old male with SS presenting with swelling of the parotid glands, redness and irritation of the eyes, polyarthralgias and polyarthritis, weight loss, exertional dyspnea, malaise, erythematous and urticarial skin lesions and enlarged lymph nodes. Laboratory tests showed hypereosinophilia (34%, total 3800/mm3), lymphopenia (2%, total 220/mm3), a positive RA factor (1:2560) and decreased C3 and C4. Biopsy of an enlarged submaxillary gland was consistent with SS. A Schirmer test showed decreased tear production. Salivary glands showed a marked decrease in uptake of radioactive (Tc99) dye. Circulating immune complexes (CIC) were markedly elevated by both C1q binding and Raji cell assays. T-cell subsets showed OKT3 = 63%, OKT4 = 32% and OKT8 = 16%. "Histamine trap" in vivo test for CIC revealed fluorescence in upper dermal blood vessels with IgM, C1q, C3 and fibrin. Biopsies of the liver, bone marrow and skin revealed eosinophilic infiltration. A notable response to therapy with high doses of corticosteroids was seen with recurrence of symptoms and laboratory abnormalities after the therapy was stopped. In conclusion, we present a case of SS which is remarkable for the age and sex of the patient, extreme hypereosinophilia, marked lymphopenia, and CIC.
Aging is associated with a decreased production of B cells by the bone marrow and an increased life-span of peripheral B cells. To determine whether the decreased bone marrow B cell production is linked to the increased life-span of B cells in old mice, B cell regeneration following lymphopenia was studied in young and old mice. The rate of bone marrow pre-B cell and of splenic B cell regeneration is slower in irradiated, old compared to irradiated, young recipients of young, congeneic bone marrow. This finding reflects an age-associated defect in the bone marrow microenvironment. As the bone marrow is the only source of a diverse population of B cells, we measured the diversity of the splenic B cell repertoire regenerated following drug-induced lymphopenia in old and young mice. The heterogeneity of mRNA size from IgH complementarity determining region 3 (CDR3) was more restricted in splenic B cells from old compared to young mice providing additional evidence for an age-associated impairment in B cell production by the bone marrow.
BACKGROUND: Although Cryptococcus neoformans is a fungal pathogen that causes human disease predominantly in the immunocompromised host, severe cryptococcal infections are occasionally encountered in apparently immunocompetent individuals. Activation of cellular immunity by proinflammatory cytokines plays a central role in anticryptococcal defense. METHODS: We describe 2 patients with severe cryptococcal meningitis who appeared to have idiopathic CD4 lymphopenia. For these patients and for 4 healthy volunteers, ex vivo stimulation of whole blood with microbial stimuli was used to investigate putative defects in cytokine production capacity. RESULTS: Assessment of the cytokine released from the 2 patients with CD4 lymphopenia revealed a defective production of the proinflammatory cytokines interferon (IFN)- gamma and tumor necrosis factor (TNF) but not of the anti-inflammatory cytokine interleukin-10 (IL-10). One patient with disease progression despite receipt of antifungal treatment was administered immunotherapy with recombinant IFN- gamma . Administration of recombinant IFN- gamma resulted in both restoration of immunological parameters and a sustained clinical recovery. CONCLUSIONS: Refractory meningitis may be due to defective TNF and IFN- gamma production, and IFN- gamma treatment may be useful in patients with an impaired cellular immune response and refractory cryptococcal meningitis.
FTY720, a potent immunomodulatory drug in phase 2/3 clinical trials, induces rapid and reversible sequestration of lymphocytes into secondary lymphoid organs, thereby preventing their migration to sites of inflammation. As prerequisite for its function, phosphorylation of FTY720 to yield a potent agonist of the sphingosine-1-phosphate receptor S1P(1) is required in vivo, catalyzed by an as-yet-unknown kinase. Here, we report on the generation of sphingosine kinase 2 (SPHK2) knockout mice and demonstrate that this enzyme is essential for FTY720 phosphate formation in vivo. Consequently, administration of FTY720 does not induce lymphopenia in SPHK2-deficient mice. After direct dosage of FTY720 phosphate, lymphopenia is only transient in this strain, indicating that SPHK2 is constantly required to maintain FTY720 phosphate levels in vivo.
BACKGROUND: Intravascular lymphoma is a proliferation of lymphoid cells, usually B cells, in small vessels, predominantly in the nervous system and skin. CASE REPORT: We report a case of a man with a 3-year history of lymphopenia with no detectable etiology (all viral causes were ruled out) who developed intravascular lymphoma in the cerebral vessels. DISCUSSION: This case was particular as the patient had idiopathic CD4+ lymphopenia. It points out the probable role of immunodepression in the development of lymphomas, particularly in endovascular localizations.
A variety of infectious agents can cause secondary immunodeficient states. We herein present a one-year-old patient, admitted to the hospital with severe lymphopenia, who was subsequently diagnosed as tuberculosis. After the antituberculosis (anti TB) therapy was started, the clinical condition and the immunologic findings of the patient improved. We have thus concluded that the transient lymphopenia of the patient was due to Mycobacterium tuberculosis. We suggest that immunodeficiency should be investigated more often in children with tuberculosis and that further studies will shed light on the pathogenesis of this aspect of the disease.
To determine whether immunosuppression by total lymphoid irradiation (TLI) slowed deterioration of chronic progressive multiple sclerosis (MS), functional impairment score and blood lymphocyte counts were compared at 6-month intervals through 4 years following treatment of MS patients by either TLI (n = 27) or sham irradiation (n = 21). At each interval, 20 to 30% fewer TLI-treated patients had deteriorated (p less than 0.05 at 6, 12, and 18 months), and the difference in mean functional impairment score between groups became progressively greater (p less than 0.01 at 42 and 48 months). Benefit accrued principally to the 17 TLI-treated patients with absolute blood lymphocyte counts less than 900/mm3 3 months after treatment, whose mean functional impairment score remained within 0.6 units of baseline (p = NS), whereas the ten TLI patients with higher post-treatment lymphocyte counts had progressive deterioration (p less than 0.05 to p less than 0.001 versus TLI-treated patients with lower lymphocyte counts at all intervals except 30 months) and had deteriorated by more than 5 functional scale units by 42 and 48 months. Side effects were minor and complications rare in TLI-treated patients, but one TLI-treated patient developed staphylococcal sepsis. Thus, TLI slows deterioration of chronic progressive MS, with what appears to be enduring benefit through 4 years compartmented to patients with greater induced lymphopenia. Modification of lymphoid irradiation regimens to increase the proportion of MS patients who achieve a favorable degree of lymphopenia and to avert functional hyposplenism may further improve the benefit/risk ratio.
Two women with Stage II breast carcinoma treated with lumpectomy followed by breast irradiation and adjuvant chemotherapy developed Pneumocystis carinii pneumonia while receiving cytotoxic chemotherapy. Neither woman had evidence of immunosuppression before therapy. They both had profound lymphopenia, reversed CD4/CD8 ratios, and normal peripheral blood total leukocyte counts at the time of their infections. Both women were seronegative for human immunodeficiency virus type 1 and had no risk factors for such an infection. The patients' CD4 lymphocyte counts increased after chemotherapy for breast carcinoma was discontinued. Thus, it appears that the therapy they received may have caused severe T-lymphocyte mediated immunosuppression.
Autoimmune gastritis, a CD4+ T cell-mediated organ-specific autoimmune disease, can be induced by thymectomy of neonatal, but not of older, BALB/c mice. Here we have shown that autoimmune gastritis can also be induced in 6-8-week-old BALB/c mice by thymectomy combined with a single dose of cyclophosphamide (300 mg/kg). This treatment reduced the numbers of splenic T and B cells approximately 25-fold. However, by 8 days after treatment, the number of splenic lymphocytes had returned to normal adult levels. Approximately 50% of treated mice developed autoimmune gastritis after 10-12 weeks. These mice had mononuclear cellular infiltrates within the gastric mucosa and serum autoantibodies to the alpha and beta subunits of the gastric H+/K+ ATPase. Transgenic mice, expressing the gastric H+/K+ ATPase beta-subunit in the thymus (Alderuccio, F., Toh, B. H., Tan, S. S., Gleeson, P. A. and van Driel, I. R., J. Exp. Med. 1993. 178: 419), did not develop autoimmune gastritis after the adult thymectomy/cyclophosphamide treatment. Thus a T cell response to the H+/K+ ATPase beta-subunit is likely to be required for the onset of gastritis. These observations suggest that pathogenic autoreactive T cells exist in the periphery of normal adult mice and that autoimmunity can be induced by the activation of these autoreactive T cells following transient lymphopenia. Cyclophosphamide-treatment of adult mice without thymectomy did not induce autoimmune gastritis, suggesting thymic regulation of these pathogenic T cells.
FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) is an orally available immunomodulatory agent that induces severe peripheral blood lymphopenia. Most studies of these lymphopenic effects have been limited to short-term exposure to FTY720. FTY720 alters the ability of lymphocytes to respond to sphingosine-1-phosphate (S1P) through S1P receptors, particularly S1P1. FTY720 affects different leukocyte populations and their trafficking through major lymphoid organs. We show the dynamics of CD4 T, CD8 T, and B lymphocyte recirculation in all major lymphoid compartments during 21-day FTY720 treatment of normal C57BL/6 mice. Following a transient increase in peripheral lymph nodes and Peyer's patches, lymphocyte recirculation reaches a new steady state. Other lymphoid organs show transient changes in lymphocyte composition with various patterns. At 21 days of FTY720 treatment, total body lymphocyte content is reduced by 20% and blood lymphocytes by 80%. Modeling suggests that the new steady state is due to a combination of reduced naive lymphocyte release from the thymus and a transient reduction of lymphocyte egress from lymph nodes. Our data indicate that the commonly held belief that FTY720 blocks lymphocyte egress from lymph nodes cannot fully explain the lymphocyte dynamics observed with prolonged treatment.
It is not known why respiratory syncytial virus (RSV) is associated with prolonged sequelae in many children. Measles virus (also a paramyxovirus), acute stress in sepsis, and cardiac bypass all cause lymphopenia. Using a retrospective analysis of records of children in Bristol with RSV infections over 5 years, we found that children with RSV had lower lymphocyte counts than unstressed, stable children prior to cardiac surgery. Children who required intensive care had the lowest lymphocyte counts. Neutrophil counts were raised in RSV-infected children. These data may offer an insight into pathological mechanisms, and suggest new research avenues.
A lymphopenia (peripheral-blood-lymphocyte count less than 1,000/mm3) was observed in seven out of ten patients with toxic epidermal necrolysis (TEN). The enumeration of T-lymphocyte subsets with monoclonal antibodies showed a decreased number of pan T-lymphocytes (OKT3-positive), which was related to a profound depletion of OKT4-positive cells. In contrast, OKT8-positive cell counts were not significantly changed. This abnormal balance of T-lymphocytes was linked to the acute phase of the disease and was not found after recovery. The pathogenetic mechanisms of such T-lymphocyte abnormalities in TEN remain unclear.