Immunosuppression Associated With Leukoproliferative Disorders*
M. Julia B. Felippe • Debra C. Sellon
Neoplastic disease can impair cell-mediated and humoral immune responses as a result of an abnormal bone marrow environment, altered patterns of cytokine production or release, or impaired proliferative responses (anergy).
In horses, immunodeficiency has most often been described in association with lymphosarcoma or plasma cell myeloma.Lymphosarcoma
Immunodeficiency has been identified in some horses with equine lymphosarcoma. The immunologic abnormality most often described is a decrease in the concentrations of serum immunoglobulins, especially IgM.1-5 Recurrent or persistent infections may occur and complicate recognition of the underlying neoplastic disorder. Neoplastic cells were suggested to be T-suppressor cells in one horse, indicating a possible mechanism for the IgM deficiency.1 Diminished lymphocyte blastogenesis responses indicative of impaired T-cell function have been described in two horses with lymphosarcoma, one of which had concurrent IgM deficiency.5 Some horses with lymphosarcoma have been diagnosed with concurrent bacterial infections, which may be related to immunosuppression.4,5 Lymphosarcoma has been associated with bone marrow necrosis in people and horses, leading to pancytopenia and sepsis, presumably due to profound neutropenia.6 Similarly, myelophthisis secondary to tumor cell infiltration of bone marrow may lead to pancytopenia and immunosuppression in horses.7,8
Plasma Cell Myeloma
Plasma cell myeloma has been reported in horses of several breeds.9 Although reports of the condition are limited, there appears to be no gender predilection. Horses have ranged in age from 3 months to 22 years (median is 11 years) at diagnosis. Common clinical signs include weight loss, anorexia, fever, pneumonia, and limb edema.
Both equine and human patients with plasma cell myelomas have an increased susceptibility to bacterial infections, probably as a result of a secondary immunodeficiency.9-11 Immune suppression in human patients with myeloma is well documented and can lead to severe infection.12 Mechanisms include abnormal Ig production, abnormal cytokine production, and dysfunctional NK cell and DC populations.12 As a malignancy of plasma cells or lymphocytoid plasma cells, plasma cell myelomas typically produce large quantities of a homogeneous immunoglobulin or immunoglobulin fragment, resulting in a monoclonal gam- mopathy. In both equine and human cases of myeloma, the predominant serum globulins are generally subclasses of IgG.9,10 Hyperglobulinemia is a characteristic but not invariable finding. Monoclonal gammopathies in the horse have also been reported with lymphoma and benign disorders.13,14 The concentrations of normal polyclonal immunoglobulins are generally decreased in myeloma patients as a result of several mechanisms, including decreased synthesis and accelerated catabolism of antibody and suppressed clonal expansion of B cells.9-11 Similar to plasma cell myeloma, certain types of B-cell lymphoma and/or leukemia can produce monoclonal gammopathies and decreased relative numbers of normal B cells and polyclonal immunoglubulins.15 Decreased numbers and dysfunction of neutrophils and defective complement activation may also contribute to the impaired immune function.Other Leukoproliferative Disorders
A wide variety of other leukoproliferative disorders have been described in horses, including acute and chronic granulocytic leukemia,16-18 myeloblastic leukemia,19 myelomonocytic leukemia,20,21 monocytic leukemia,22 eosinophilic myeloproliferative disorder,23 and malignant histiocytosis.24 Regardless of the primary cell line of origin, the end result is often myelophthisis and pancytopenia with the potential for significant immunosuppression.
A horse with myelomonocytic leukemia was diagnosed with pulmonary aspergillosis.25Immunosuppression Associated With Infectious Agents or Processes significant clinical problems include pneumonia, septic arthritis, and diarrhea. This syndrome should be distinguished from the glossitis caused by Candida infection seen in inappetent or debilitated neonatal foals, which is fairly common and generally resolves with amelioration of the primary disease.12 Regardless of cause or underlying nature of the immunodeficiency, the prognosis for foals with oral candidiasis and associated bacterial septicemia is guarded to poor.
Immunosuppression may also occur secondary to corticosteroid administration, which is discussed in detail earlier in this chapter. Corticosteroid therapy results in lymphopenia, suppression of macrophage phagocytic function, impaired killing of ingested organisms, impaired secretion of monokines, and inhibited antigen processing and presentation.13,14 Cell-mediated immunity is impaired through T-cell lymphopenia, altered cytokine production, and decreased antigen presentation, and it is reflected in the suppression of mitogen stimulation responses. Humoral immunity is impaired indirectly through altered T-cell responses, enhanced Ig catabolism, and decreased antigen presentation.13 Horses receiving high or prolonged therapy with corticosteroids have been reported to experience exacerbations of preexisting infections or decreased resistance to newly encountered pathogens.15,16 This may manifest as bacterial pneumonia or pleuropneumonia, candidiasis and other fungal infections, equine protozoal myeloencephalitis, or a variety of other infectious disorders.11,16
Infections That Cause Immune Suppression
Some infectious agents have developed strategies to elude immune defenses in hosts with otherwise normal, functioning immune systems. These strategies may downregulate immune responses to the extent that the host becomes vulnerable to secondary infection.
Many viral, fungal, and bacterial infections transiently suppress specific and nonspecific immune responses, predisposing animals to secondary bacterial infections.17 Severe endotoxemia or septicemia may suppress neutrophil numbers and bactericidal function, predisposing to secondary infection.EQUINE INFLUENZA. Although little work has been done to specifically examine the effects of equine influenza viruses on the equine immune system, it is widely acknowledged that this viral infection predisposes horses to secondary bacterial infection.18,19 Proposed mechanisms for increased susceptibility to bacterial infection after influenza infection include disruption of the barrier function of respiratory epithelium, exposing bacterial adhesion molecules; desensitization of alveolar macrophages to bacterial Toll-like receptor ligands; and alteration of immune 2021 functions in the alveolar microenvironment.20,21
PERINATAL EQUINE HERPESVIRUS TYPE 1 INFECTION. Infection of the fetus with equine herpesvirus type 1 (EHV-1, rhinopneumonitis) late in gestation has been associated with death or postnatal development of interstitial pneumonia, lymphopenia, marked necrosis and atrophy of the thymus and splenic lymphoid tissue, and increased susceptibility to bacterial infections.22 Despite apparently adequate passive transfer of maternal antibody, affected foals contract a variety of infectious bacterial diseases, including colibacillosis, streptococcal septicemia, salmonellosis, and Tyzzer's disease. EHV-1 is isolated from nasal passages in about 30% of the cases. The spleen and thymus are grossly small at necropsy. Bilateral adrenocortical hyperplasia is noted in most foals. Histologically, splenic periarteriolar lymphocytic sheaths are depleted of lymphocytes, and no lymphoid follicles are detectable. Thymic alterations vary from extreme diminutions of thymocyte numbers to complete necrosis of thymic lymphocytes with disappearance of Hassall's corpuscles and disruption of the epithelial matrix.
Lymph nodes also show lymphoid necrosis. An immunodeficiency secondary to the marked lymphoid damage induced by the virus is credited with allowing secondary bacterial infections to become established. Immunization of broodmares against EHV-1 would seem to be the most appropriate approach to prevention.EQUINE HERPESVIRUS TYPE 5 INFECTION. Equine herpesvirus type 5 (EHV-5) is an emerging pathogen linked to equine multinodular pulmonary fibrosis (EMPF).23-26 This gammaherpesvirus has been found in bone marrow of infected horses, contributing to speculation that the virus may be immunosup- pressive.25,26 Many affected horses are lymphopenic for undetermined reasons, most are anemic and thrombocytopenic, and at least one affected horse was profoundly pancytopenic, leading to speculation that immune-mediated or direct viral destruction of mature cells and/or hematopoietic precursors in the bone marrow may play a role in diminished cell counts in peripheral blood.23-25 Transient improvement in cell counts after initiation of corticosteroid therapy supports the possibility of immune-mediated mechanisms for destruction of hematopoietic cells.25 One case of EMPF presented with primary lymphocytic leukemia, generalized lymphadenopathy, and infiltration of neoplastic lymphocytes in bone marrow, lymph nodes, and spleen.26 Infiltrating cells were almost exclusively T lymphocytes, whereas B lymphocytes could not be detected. Depletion of B-cell lines was accompanied by hypogammaglobulinemia.26 EHV-5 infection was demonstrated in lung, bone marrow, and lymph nodes.26 A link between the T-cell leukemia and infection by EHV-5 was suggested.