Hemophagocytic syndrome in a cat with Mycoplasma haemofelis infection.

A six-year-old, castrated male domestic shorthair cat was presented for a week-long history of lethargy, acute anorexia, and adipsia. On presentation, the cat was weak with pale mucous membranes, open-mouth breathing, and mild popliteal lymphadenomegaly. Routine bloodwork revealed bicytopenia due to marked non-regenerative anemia and moderate thrombocytopenia; erythrocyte clumping was apparent on the blood smear, but no agglutination was noted on a saline dispersion test. Abdominal and thoracic imaging showed marked splenomegaly and multiple mildly enlarged lymph nodes. Aspirates from the bone marrow and spleen contained many erythrophagocytic macrophages and occasional lymphocytes containing engulfed erythrocytes. The macrophages also occasionally contained phagocytosed erythroid precursors, platelets, and leukocytes. A diagnosis of hemophagocytic syndrome was made based on the presence of bicytopenia and increased numbers of hemophagocytic macrophages in the spleen and bone marrow. Though no organisms were observed, Mycoplasma spp. infection was suspected and confirmed via PCR. To the authors' knowledge, this is the first report of a hemophagocytic syndrome in a cat with Mycoplasma haemofelis. Lymphocyte engulfment of erythrocytes has been previously reported in a cat with M. haemofelis infection. Both hemophagocytic syndrome and engulfment of erythrocytes by lymphocytes should prompt testing for Mycoplasma spp. even with a lack of evident parasitemia.

Presumptive hemophagocytic syndrome associated with co-infections with FIV, Toxoplasma gondii, and Candidatus mycoplasma haemominutum in an adult cat.

A 9-year-old neutered male cat, previously test-positive for feline immunodeficiency virus (FIV), was presented with an history of vomiting, hyporexia, and weight loss. Panleukopenia was identified on complete blood counts, and bone marrow evaluation revealed ineffective granulocytic hyperplasia and rare neutro-, erythro-, and rubriphagocytosis. Prednisolone was initiated with no response, and progression to pancytopenia occurred. On abdominal ultrasonographic examination, splenomegaly was present. PCR testing was positive for Candidatus Mycoplasma haemominutum and IgG antibodies against Toxoplasma gondii were detected (titer 1:2560). Treatment with antibiotics, feline recombinant interferon-ω, chlorambucil, mycophenolate, and raltegravir was implemented with no clinical improvement, and splenectomy was performed. Cytologic evaluation of splenic aspirates revealed exuberant neutro-, erythro-, and rubriphagocytosis. Histopathology of the spleen also showed many erythrophagocytic macrophages with no evidence of malignancy, and a diagnosis of hemophagocytic syndrome (HS) was made. The WBC count and hematocrit reached reference values 1 day and 3 months, respectively, after splenectomy. The cat was treated with cyclosporine and lomustine. Disease progression led to the development of septic hepatitis, and the cat was euthanized. To our knowledge, this is the first case of presumptive HS in cats that might have been associated with FIV, Toxoplasma gondii, and Candidatus Mycoplasma haemominutum co-infection.

Hemophagocytic syndrome in a cat with immune-mediated hemolytic anemia.

A 10-year-old spayed female domestic short-haired cat presented with depression, anorexia, and tachypnea. A complete blood count revealed moderate regenerative anemia, severe leukopenia, and mild thrombocytopenia. Antibodies against feline immunodeficiency virus (FIV) were also detected. Abdominal radiography and ultrasonography revealed severe splenomegaly. Cytologic evaluation of the spleen revealed macrophagic infiltration with hemophagocytosis. Bone marrow aspiration revealed erythroid hyperplasia with no other abnormalities. A presumptive diagnosis of hemophagocytic syndrome secondary to immune-mediated hemolytic anemia was made based on a positive direct Coombs test result. Blood transfusion, prednisolone, and immunosuppressive treatments were performed; however, the blood abnormalities did not improve. The cat was then administered prednisolone and chlorambucil, followed by splenectomy. Leukopenia immediately recovered, and packed cell volume increased slightly. However, the blood abnormalities recurred, and the cat died. To the best of our knowledge, this is the first report of hemophagocytic syndrome secondary to immune-mediated disease in an FIV-positive cat.

Hemophagocytic syndrome associated with large granular lymphoma in an adult dog.

Hemophagocytic syndrome (HPS) is a rare disorder characterized by dysregulation of the immune response resulting in uncontrolled activation of macrophages with exacerbated phagocytosis of host cells. In dogs, the criteria for diagnosis include the presence of pancytopenia or bicytopenia in the peripheral blood and >2% hemophagocytic macrophages in bone marrow aspirates. When HPS is associated with lymphoma, it is called lymphoma-associated hemophagocytic syndrome (LAHS). Here, we present a case of a 4 ½-year-old female spayed Old English Mastiff that presented with severe thrombocytopenia, mild anemia, mild to moderate leukopenia, and large granular lymphocytes (LGLs) in the peripheral blood. The patient had enlarged lymph nodes with many LGLs seen cytologically, leading to the interpretation of LGL lymphoma. Bone marrow displayed numerous LGLs that stained strongly for CD3 but did not show immunoreactivity to CD4 or CD8, and PCR for antigen receptor rearrangement analysis confirmed a clonal T-cell receptor gamma gene rearrangement. The presence of ~3.5% hemophagocytes present on the bone marrow evaluation raised concern for HPS and, more specifically, LAHS. HPS and LAHS are challenging to diagnose and require many criteria to be fulfilled before a definitive diagnosis can be made; the low number of cases in the literature makes this even more challenging in dogs. This case represents secondary LAHS due to LGL lymphoma in a dog.

T-cell lymphoma-associated hemophagocytic syndrome in an American Pit Bull Terrier.

A 3-y-old, intact female, American Pit Bull Terrier was presented because of acute onset of anorexia and a large subcutaneous submandibular mass that had been present for 3 wk. The submandibular mass, 2 engorged black-legged ticks on the dorsum of the neck, pyrexia, and icterus were seen on physical examination. Abnormal laboratory test results included a positive Anaplasma antibody test, severe thrombocytopenia, mild nonregenerative anemia, hyperbilirubinemia, and elevated liver enzyme activities. Cytology of the mass was interpreted as marked septic purulent inflammation with acute hemorrhage. Treatment with doxycycline for anaplasmosis was unsuccessful, and the patient died at an emergency follow-up visit 2 d after the initial presentation. Autopsy and histopathology revealed widespread metastasis of a presumptive histiocytic neoplasm with associated hemophagocytosis seen in lymph nodes (LNs), liver, and spleen. Immunohistochemistry yielded a definitive diagnosis of a CD3+/CD18+ T-cell lymphoma. In this case of canine lymphoma-associated hemophagocytic syndrome, hemophagocytes were observed as >2% of neoplastic cells in the liver, spleen, and LN histologically, a scarce or unreported finding, to our knowledge. The prognosis was grave, with a short survival time after the onset of clinical signs.

Presumptive hemophagocytic syndrome associated with immune-mediated anemia in two Miniature Dachshunds.

This report describes the cases of two Miniature Dachshunds who were suspected to have immune-mediated hemolytic anemia (IMHA) and were treated with immunosuppressive therapy. However, progression of anemia, increases in C-reactive protein (CRP) and total-bilirubin (T-Bil) levels, splenomegaly, transition to nonregenerative anemia, and thrombocytopenia occurred after the treatment. Splenectomy and bone-marrow aspirations were performed subsequently. Both dogs were diagnosed with hemophagocytic syndrome (HPS) associated with IMHA. Unfortunately, they died 9 and 6 days later. These findings indicate that some cases of refractory IMHA have the pathogenicity of HPS. HPS should be included as a differential diagnosis of refractory IMHA concurrent with thrombocytopenia. Continuously elevated CRP and T-Bil levels may be helpful indicators in the detection of HPS associated with IMHA.

Development of Mast Cell and Eosinophil Hyperplasia and HLH/MAS-Like Disease in NSG-SGM3 Mice Receiving Human CD34+ Hematopoietic Stem Cells or Patient-Derived Leukemia Xenografts.

Immunocompromised mouse strains expressing human transgenes are being increasingly used in biomedical research. The genetic modifications in these mice cause various cellular responses, resulting in histologic features unique to each strain. The NSG-SGM3 mouse strain is similar to the commonly used NSG (NOD scid gamma) strain but expresses human transgenes encoding stem cell factor (also known as KIT ligand), granulocyte-macrophage colony-stimulating factor, and interleukin 3. This report describes 3 histopathologic features seen in these mice when they are unmanipulated or after transplantation with human CD34+ hematopoietic stem cells (HSCs), virally transduced hCD34+ HSCs, or a leukemia patient-derived xenograft. The first feature is mast cell hyperplasia: unmanipulated, naïve mice develop periductular pancreatic aggregates of murine mast cells, whereas mice given the aforementioned human cells develop a proliferative infiltrative interstitial pancreatic mast cell hyperplasia but with human mast cells. The second feature is the predisposition of NSG-SGM3 mice given these human cells to develop eosinophil hyperplasia. The third feature, secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS)-like disease, is the most pronounced in both its clinical and histopathologic presentations. As part of this disease, a small number of mice also have histiocytic infiltration of the brain and spinal cord with subsequent neurologic or vestibular signs. The presence of any of these features can confound accurate histopathologic interpretation; therefore, it is important to recognize them as strain characteristics and to differentiate them from what may be experimentally induced in the model being studied.

A case of hemophagocytic syndrome progressing into large granular lymphoma in a dog.

A 12-year-old castrated male mixed breed dog was presented with anorexia, lethargy, intermittent vomiting, diarrhea, and weight loss. Clinicopathologic and imaging abnormalities included pancytopenia, icterus, and splenomegaly with multiple minute hypoechogenic nodules. Bone marrow (BM) smears revealed 2.5% hemophagocytic macrophages. In addition, an increased number of small to intermediate lymphocytes (16.3%) and plasma cells (3.2%) were recognized in the BM smears. More than 80% of the lymphocytes contained multiple small intracytoplasmic magenta granules. Histopathologic findings of the spleen revealed hemophagocytosis. Large granular lymphocytes (LGLs) were not found on the liver cytology or splenic histopathology at this time. PCR for antigen receptor rearrangement (PARR) analysis showed a clonal reaction in the T-cell receptor ɤ (TCRɤ) gene in the BM sample. The dog was diagnosed with hemophagocytic syndrome (HPS). The dog was maintained in good condition with immunosuppressive therapy. However, the dog developed hepatic LGL lymphoma 7 months later. At this time, PARR analysis showed a clonal TCRɤ gene rearrangement in the hepatic LGL lymphoma samples. The BM and liver sample clonal rearrangements showed 100% homology, indicating that the small to intermediate granular lymphocytes in the BM at the HPS stage had progressed to hepatic LGL lymphoma. To our knowledge, this is the first report of canine secondary HPS caused by the occurrence of a BM LGL lymphoma clone that progressed to hepatic LGL lymphoma.

Lomustine chemotherapy for the treatment of presumptive haemophagocytic histiocytic sarcoma in Flat-coated Retrievers.

BACKGROUND: The Flat-coated Retriever (FCR) is a breed at-risk for histiocytic sarcoma (HS). A haemophagocytic form of HS (HPHS) occurs in the spleen ± other sites such as bone marrow, and is a CD11d+ disease of macrophage origin. Patients with HPHS typically present with regenerative anaemia. Lomustine is a well-accepted, first-line chemotherapy for dogs with HS, but its specific utility in dogs with HPHS has not been previously reported. METHODS: A cohort of 10 dogs presumptively diagnosed with HPHS via splenic ± bone marrow or liver aspiration cytology were treated with lomustine, plus supportive medications as required. Cytology of liver and bone marrow was diagnostically useful in patients where splenic cytology was less convincing. RESULTS: No dogs experienced significant constitutional or gastrointestinal adverse effects following lomustine administration, though most dogs displayed clinical signs associated with the underlying disease. No patients appeared to derive discernible clinical benefit from chemotherapy. Neutropenia was a common adverse effect of lomustine. Concurrent medications included corticosteroids in all cases, prior to the diagnosis of HPHS, for a provisional diagnosis of immune-mediated haemolytic anaemia. Median survival time of the treated dogs was 24 days from diagnosis (range, 4-67 days). CONCLUSIONS: HPHS affecting FCRs appears to have a uniformly poor outcome and is rapidly fatal. Lomustine chemotherapy was unsuccessful in significantly improving outcome in this cohort of patients. Further study of this rare and devastating disease is needed.

Lymphoma-associated hemophagocytic syndrome in six dogs.

Hemophagocytic syndrome (HPS) is a clinicopathological entity characterized by histiocytic proliferation, with marked hemophagocytosis in the reticuloendothelial organs. HPS caused by lymphoma is termed lymphoma-associated hemophagocytic syndrome (LAHS), and there are few reports on canine and feline LAHS. The objective of this study was to examine the clinical, diagnostic, and clinicopathologic features of LAHS in six dogs. The diagnostic criteria of LAHS consisted of lymphoma, bicytopenia or pancytopenia in the blood, and increased hemophagocytosis in the reticuloendothelial organs. In one dog, an ocular form of lymphoma was recognized. A splenic form was recognized in two dogs, and a hepatosplenic form was recognized in three dogs. Immunophenotyping revealed T-cell origin in five dogs and B-cell origin in one dog by polymerase chain reaction for antigen receptor rearrangement analysis. Nonspecific esterase stain was performed to differentiate between neoplastic lymphocytes and hemophagocytes. All five dogs with T-cell lymphoma were diagnosed with large granular lymphocyte (LGL) lymphoma. In three cases, palliative therapy with glucocorticoids was conducted, while the other three cases received chemotherapy as well. The survival times for the three dogs with glucocorticoids only were 6, 6, and 10 days and were 30, 54, and 68 days for the three treated with anticancer therapy. The median survival time for the dogs was 20 days. This report indicates that canine LAHS is likely to be caused by LGL lymphoma, and it has an aggressive behavior and poor general prognosis, as seen in humans.

Hemophagocytic lymphohistiocytosis in acute African swine fever clinic.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) usually has been defined as the combination of a proliferation of cytologically benign, actively phagocytic macrophages in bone marrow, spleen, lymph nodes, etc. in association with fever, cytopenia, splenomegaly, and hypertriglyceridemia. HLH is often triggered by viral infection. The aim of this study was to ascertain the features of HLH involvement in African swine fever virus (ASFV) (genotype II) pathogenesis. METHODS: The serum levels of macrophage colony-stimulating factor (MCSF) and granulocyte-macrophage colony-stimulating factor (GMCSF), as well as the histological constitution (for hemophagocytic macrophages detection) of various organs of pigs infected with ASFV genotype II were investigated. The diagnosis of HLH was made according to universally accepted human criteria. RESULTS: The association of fever, cytopenias, splenomegaly, and hemophagocytosis was present in 87.5% of the infected pigs (absence of hyperthermia in one of eight pigs). Marked hypertriglyceridemia was observed at 3-4days post infection. Previously it was shown that ASFV induced a significant decrease in the level of fibrinogen from day 5 till the end of experiment. Progression of the HLH coincided with a temporary increase in the serum levels of MCSF levels (early stage of disease) and GMCSF levels (2-3 pays post infection). CONCLUSIONS: Hemophagocytic syndrome should be suspected in ASFV (genotypeII) infected pigs.

Hemophagocytic syndrome in a cat with multiple myeloma.

An 11-year-old, castrated male, Domestic Medium Hair cat was presented to the University of Florida Small Animal Hospital with a 2-week history of upper respiratory infection and increased serum globulins, as reported by the referring veterinarian. Physical examination was unremarkable other than melanosis of the left iris, with no evidence of ocular, nasal, or respiratory disease. Laboratory abnormalities included moderate nonregenerative anemia, mild leukopenia, mild hyperfibrinogenemia, severe hyperglobulinemia, mild hypoalbuminemia, and hypocholesterolemia. Abdominal radiographs and ultrasonographic examination revealed mild splenomegaly with no other abnormalities. Thoracic radiographs revealed no abnormalities. Cytologic evaluation of fine-needle aspirates from the spleen, liver, and bone marrow revealed numerous plasma cells and many vacuolated macrophages exhibiting marked phagocytosis of mature erythrocytes and platelets, occasionally metarubricytes and leukocytes, and rarely plasma cells. The cytologic interpretation was multiple myeloma and associated hemophagocytic syndrome (HPS). Serum protein electrophoresis revealed a monoclonal gammopathy, providing further evidence for a multiple myeloma. To the authors' knowledge, this is the first report of HPS secondary to neoplasia in a cat.

[Reactive and neoplastic histiocytic diseases in the dog]. / Reaktive und neoplastische histiozytäre erkrankungen beim hund.

There are different histiocytic diseases in dogs that are characterized by the proliferation of histiocytic cells (macrophages and myeloid dendritic cells). Histiocytic diseases can be devided into neoplastic (cutaneous histiocytoma complex, histiocytic sarcoma, dendritic cell leukaemia) and reactive forms (reactive histiocytosis, haemophagocytic syndrome). All subtypes of the cutaneous histiocytoma complex (cutaneous histiocytoma, metastatic histiocytoma and Langerhans' cell histiocytosis) are of Langerhans' cell origin. Histiocytoma, which is a solitary tumour of the skin in young dogs, shows spontaneous regression in most cases. Occasionally, metastasis to lymph nodes can be seen (metastatic histiocytoma). Only one dog with Langerhans' cell histiocytosis has been described and was euthanized. Histiocytic sarcoma, which arises from myeloid dendritic cells, can be classified as localised histiocytic sarcoma or disseminated histiocytic sarcoma. Another form of histiocytic sarcoma - haemophagocytic histiocytic sarcoma - is derived from macrophages. Histiocytic sarcoma displays a very aggressive clinical course and has a poor prognosis. Breed predispositions have been reported for the disseminated and haemophagocytic form of histiocytic sarcoma in Bernese mountain dogs, Rottweilers and varoiusretrievers. In contrast, reactive histiocytosis (cutaneous and systemic forms) develops by reactive proliferation of interstitial dendritic cells. In systemic histiocytosis, breed predilections are similar to histiocytic sarcoma. Haemophagocytic syndrome develops as a consequence of proliferation of activated macrophages in different tissues. Prognosis in general is moderate to poor and depends on the origin of the underlying disease process.

Hemophagocytic syndrome in a pancytopenic simian retrovirus-infected male rhesus macaque (Macaca mulatta).

Hemophagocytic syndrome (HPS) is a macrophage hyperactivation disorder triggered by disrupted T-cell macrophage cytokine interaction. HPS has been reported in humans, dogs, cats, and cattle, and it is infrequent and poorly characterized in animals. A 16-year-old male rhesus macaque was euthanized because of severe pancytopenia, including nonregenerative anemia (hematocrit = 5.5%), neutropenia (0.29 K/µl), and thrombocytopenia (21 K/µl). Bone marrow was hypocellular with normal maturation, myeloid hypoplasia, and few megakaryocytes. There were numerous morphologically normal macrophages (12% of nucleated cells), with 6% of nucleated cells being hemophagocytic macrophages in the bone marrow. Serology was negative, but polymerase chain reaction and immunohistochemistry were positive for simian retrovirus type 2. Blood and bone marrow findings were consistent with HPS. Cytopenias are common in simian retrovirus-infected macaques, but HPS has not been reported. An association between simian retrovirus infection and HPS is undetermined, but retrovirus-associated HPS has been observed in humans.

Structure and sequence variation of the canine perforin gene.

Lymphocyte-mediated cytotoxicity is essential to control viral infections, limit lymphocyte expansion and activation, and survey for malignant cells. Humans with defects in lymphocyte cytotoxicity have reduced perforin function resulting in uncontrolled lymphocyte expansion, leading to excessive histiocyte activation and a hemophagocytic disorder. Dog breeds such as Bernese mountain dogs (BMD) have a high incidence of reactive and malignant diseases affecting histiocytes. This study addressed the hypothesis that changes in the perforin gene contribute to the development of hemophagocytic histiocytic sarcoma (HHS) in BMD. Canine perforin DNA was amplified and sequenced through multiple PCR assays from healthy and diseased dogs, and the gene structure determined by rapid amplification of cDNA ends. The coding component of the gene consists of 1679bp, with two exons of 536bp and 1143bp separated by an intron of 865bp. Gene configuration and location differ from that in other species although the coding sequence is highly conserved. Three silent single nucleotide polymorphisms (SNP) were identified. Analysis of their distribution indicated a consistent genotype among 6 middle-aged to older BMD without histiocytic diseases. Among samples from 10 dogs with HHS and 10 without histiocytic diseases SNP occurred with variable frequency. It was concluded that changes in the amino acid sequence of perforin were not associated with HHS but that a constellation of SNP may characterize BMD without histiocytic disease. Investigation of more dogs is required to confirm a specific genotype. Future studies should focus on the potential contribution of reduced perforin expression and/or function to HHS in dogs.

Disseminated histiocytic sarcoma with excessive hemophagocytosis in a cat.

A 10-year-old Japanese domestic cat was presented with anorexia and weight loss. Severe anemia and thrombocytopenia were detected. Abdominal radiography and ultrasonography revealed the presence of multiple masses in the spleen. Cytological analyses of the masses revealed several atypical histiocytic cells and considerable hemophagocytosis. A splenectomy was performed, and the mass was diagnosed as histiocytic sarcoma on the basis of histopathological, cytochemical and immunohistochemical analyses. Further, abnormal hemophagocytosis was observed in the bone marrow. The cat was administered prednisolone and lomustine, and it survived for 107 days after admission. An autopsy revealed the presence of neoplastic histiocytic cells in the bone marrow, liver, pancreatic lymph node and glomeruli. This is the first case of histiocytic sarcoma in a cat to be reported in Japan.

Histiocytic sarcoma of macrophage origin in a cat: case report with a literature review of feline histiocytic malignancies and comparison with canine hemophagocytic histiocytic sarcoma.

Mild nonregenerative anemia was detected in a 9-year-old neutered male domestic shorthair cat during a routine examination. Bone marrow core biopsy revealed erythroid hyperplasia; however, a specific cause was not identified. Over the next 8 months the anemia progressed, eventually becoming mildly regenerative, and moderate thrombocytopenia developed. On ultrasonographic examination, marked splenomegaly, mild hepatomegaly, and abdominal lymphadenopathy were found. Cytologic evaluation of splenic aspirates revealed increased numbers of mildly to moderately pleomorphic histiocytes that frequently had phagocytosed RBCs, leukocytes, and occasionally platelets. Histopathologic examination of the spleen and liver revealed effacement of splenic architecture by a histiocytic sarcoma (HS), and neoplastic histiocytes in hepatic sinusoids. A second bone marrow aspirate revealed neoplastic infiltration by similar cells. The histiocytes in all tissues were mildly to moderately pleomorphic and markedly erythrophagocytic. The immunophenotype of histiocytes in the spleen was CD1c(-)/CD11b(+)/CD18(+)/MHC-II(+), supporting a macrophage cell lineage. The clinical, pathologic, and immunophenotypic findings in this cat were similar to those in hemophagocytic HSs in dogs. To our knowledge, this is the first report of a HS of purported macrophage phenotype in a cat.

Hemophagocytic syndrome in dogs: 24 cases (1996-2005).

OBJECTIVE: To determine the frequency, potential causes, and clinical and clinicopathologic features of hemophagocytic syndrome in dogs. DESIGN: Retrospective study. ANIMALS: 24 client-owned dogs. PROCEDURES: Records for dogs in which diagnostic bone marrow specimens (including an aspiration smear and core biopsy material) were obtained from 1996 to 2005 were reviewed. Inclusion criteria were presence of bicytopenia or pancytopenia in the blood and > 2% hemophagocytic macrophages in the bone marrow aspirate. RESULTS: Of 617 bone marrow specimens evaluated, evidence of hemophagocytic syndrome was detected in 24 (3.9%). The Tibetan Terrier breed was overrepresented among dogs with hemophagocytic syndrome. Clinical signs associated with hemophagocytic syndrome included fever, icterus, splenomegaly, hepatomegaly, and diarrhea. Hemophagocytic syndrome was associated with immune-mediated, infectious, and neoplastic-myelodysplastic conditions and also occurred as an idiopathic condition. Overall, dogs with infection-associated hemophagocytic syndrome had better 1-month survival rates than dogs with immune-associated and idiopathic hemophagocytic syndrome. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that hemophagocytic syndrome may occur more frequently in dogs than has previously been suspected on the basis of the paucity of reported cases. Although most dogs had definable underlying disease conditions, idiopathic hemophagocytic syndrome was also identified. Hemophagocytic syndrome of any cause is potentially life-threatening; however, the prognosis should be adjusted on the basis of the associated disease process and potential for successful treatment.

Bovine trypanotolerance: A natural ability to prevent severe anaemia and haemophagocytic syndrome?

Trypanotolerance is the capacity of certain West-African, taurine breeds of cattle to remain productive and gain weight after trypanosome infection. Laboratory studies, comparing Trypanosoma congolense infections in trypanotolerant N'Dama cattle (Bos taurus) and in more susceptible Boran cattle (Bos indicus), confirmed the field observations. Experiments using haemopoietic chimeric twins, composed of a tolerant and a susceptible co-twin, and T cell depletion studies suggested that trypanotolerance is composed of two independent traits. The first is a better capacity to control parasitaemia and is not mediated by haemopoietic cells, T lymphocytes or antibodies. The second is a better capacity to limit anaemia development and is mediated by haemopoietic cells, but not by T lymphocytes or antibodies. Weight gain was linked to the latter mechanism, implying that anaemia control is more important for survival and productivity than parasite control. Anemia is a marker for a more complex pathology which resembles human haemophagocytic syndrome: hepatosplenomegaly, pancytopenia and a large number of hyperactivated phagocytosing macrophages in bone marrow, liver and other tissues. Thus, mortality and morbidity in trypanosome-infected cattle are primarily due to self-inflicted damage by disproportionate immune and/or innate responses. These features of bovine trypanotolerance differ greatly from those in murine models. In mice, resistance is a matter of trypanosome control dependent on acquired immunity. However, a model of anaemia development can be established using C57BL/6J mice. As in cattle, the induction of anaemia was independent of T cells but its development differed with different trypanosome strains. Identification of the molecular pathways that lead to anaemia and haemophagocytosis should allow us to design new strategies to control disease.