Foal Immunodeficiency Syndrome

M. Julia B. Felippe

■ Definition and Etiology Foal immunodeficiency syndrome (FIS), previously known as Fell Pony syndrome and also referred to as “anemia, immunodeficiency, and peripheral ganglionopathy,” is an inheritable and fatal condition character­ized by profound anemia and septicemia, the latter due to a primary immunodeficiency.

■ Clinical Findings, Clinical Signs, and Differential Diagnoses FIS-affected foals are born apparently healthy but rapidly fail to thrive. The fatal illness becomes clinically apparent in foals within 1 month, and death occurs generally by 3 months of life due to a primary, profound, nonregenerative anemia and B-cell lymphopenia, with increased susceptibility to opportunistic infections and septicemia.

The foals present with weight loss and dullness, pale mucous membranes, and signs of infection, including diarrhea and pneumonia.^2-4 Enterocolitis, bronchopneumonia, pancreatitis, and glossal hyperkeratosis are often caused by opportunistic infections (e.g., Escherichia coli, Cryptosporidium spp., adenovirus). The severe, progressive anemia results from lack of erythrocyte production in the bone marrow (nonregenerative), and it is not associated with hemorrhage or hemolysis.^2,3,5

■ ClinicalPathology At birth, blood work may be normal, with normal or borderline low erythrocyte counts and hemo­globin values and normal distribution of neutrophils and lymphocytes.⁵ When infections are present, abnormalities in the leukogram, including regenerative neutropenia or neutro­philia, toxic changes in neutrophils, and lymphopenia, may be present, and values vary depending on the type and phase of infection.

Severe normocytic or macrocytic anemia develops rapidly. Based on bone marrow cytology, FIS-affected foals may be born with erythroid precursors but rapidly evolve to erythrocyte hypoplasia. At birth, hemoglobin and hematocrit values may be measured in the low end of the normal reference range, and peripheral blood B-cell distribution may be equivalent to that of healthy, unaffected foals. In a few weeks, profound anemia and B-cell lymphopenia develop. In time, cytologic evaluation of the marrow reveals differentiating myeloid precur­sors, megakaryocytes, and/or paucity of hematopoietic precur­sors. When present, proerythroblasts have been described to be binucleate.⁴

■ Immunologic Findings Absolute lymphopenia in FIS- affected foals likely reflects poor lymphocyte development in primary and secondary lymphoid tissues, as well as failure of lymphocyte population expansion with age.^6,7 B-cell distribution in blood may be within normal or low-normal values at birth but rapidly declines in the first few weeks of life.^5,8 Although CD4+ and CD8+ T-cell distributions have been reported as normal in affected foals, T-cell dysfunction is suggested by the small thymus and opportunistic infections with cryptospo­ridia and adenovirus.^7,9 The expression of MHC class II molecules in peripheral blood lymphocytes may be decreased and/or fail to increase with age in FIS-affected foals when compared with healthy foals, also supporting abnormal lym­phocyte development.¹⁰ Nevertheless, when stimulated in vitro, the peripheral blood lymphocytes of affected foals respond normally to mitogens PHA, concanavalin A (ConA), and pokeweed mitogen (PWM).^4,7

Although the B-cell lymphopenia limits the ability of FIS- affected foals to produce immunoglobulins, serum IgG con­centrations are often normal when clinical signs are detected due to the presence of circulating colostrum-derived antibodies.^2-4,11 Nevertheless, serum IgM concentration (a parameter not confounded by colostrum-derived antibodies at this age) is low or not detectable in affected FIS-affected foals and strongly suggests impaired primary humoral immune response.^5,11,12 FIS-affected foals develop septicemia despite normal (colostrum-derived) serum IgG concentrations, sug­gesting a broad lymphocytic dysfunction.^4,5

The distribution and function of neutrophils have been reported as normal, including the presence of bands and normal oxidative burst activity.⁴

■ Pathophysiology Bone marrow cytologic studies per­formed prospectively in affected foals immediately after birth and before clinical signs became evident at a later age revealed evidence of initial erythroid hyperplasia with dysplasia, followed by a rapid and progressive hypoplasia and aplasia, as well as marked anemia.⁵ In addition, a concomitant mild myeloid dysplasia could be observed, which questions the involvement of further types of cells.

The presence of erythrocytes and B cells in peripheral blood at birth suggests a limited hematopoiesis during fetal life. Nevertheless, this cell production is not sustained after birth, leading to a marked and progressive anemia and B-cell lym­phopenia in the perinatal phase, corresponding clinical signs, and death. Erythrocytes and B lymphocytes are the most severely affected cell populations in FIS, and both undergo critical developmental stages in the bone marrow. The condition may be caused by independent or common genetic abnormalities that affect both cell lines. Most early B-cell differentiation essential genes and genes associated with erythropoiesis are expressed in the affected foals, and a potential common hematopoietic genetic defect is still under investigation.

■ Epidemiology FIS is a genetic and inheritable fatal immunodeficiency condition that occurs in male and female young foals of the Fell and Dales breeds and potentially in other breeds that include common ancestors.^13,14

The Fell Pony breed experienced loss of genetic diversity due to the small numbers of animals and overuse of prominent stallions, which likely led to the spread of the genetic defect. Pedigree analysis of the Fell Pony breed suggests that FIS may have an autosomal recessive inheritance. Carriers are phenotypically normal. FIS was initially described in the United Kingdom and subsequently in Fell Pony foals in the United States, Czech Republic, and Netherlands.^2,4,15,16

■ Necropsy Findings In the postmortem, abnormal gross findings include generalized tissue pallor, thymic hypoplasia, and inflammation and lymphadenopathy associated with infections of many organs (e.g., necrotizing enteritis, pyogranulomatous bronchopneumonia, pancreatitis, myocarditis). The medullary cavities of bones often do not contain marrow but instead pale, tan, fatty tissue, a striking finding in early age. Histopathology reveals severe erythroid hypoplasia, with small numbers or absent late erythroid precursors in the bone marrow, and high myeloid-to-erythroid ratio (ranging from 16 to 32 : 1, compared with the normal myeloid-to-erythroid ratio of 0.5 to 1.5:1).

Despite lymphadenopathy, there is severe lymphocytic hypoplasia and lack of secondary lymphoid follicles in the lymphoid tissues; in addition, plasma cells are absent. Immu­nohistochemical staining detects no B lymphocytes in the bone marrow and rare or few B cells in the lymph nodes and spleen, dispersed in the tissues without forming germinal centers. In addition, peripheral ganglionopathy characterized by neuronal chromatolysis involving trigeminal, cranial mesenteric, and dorsal root ganglia has been reported.²

■ Treatment and Prognosis FIS is a fatal disease, and foals die or are submitted to euthanasia soon after the initial clinical signs. Management of infections and septicemia may be temporarily possible with antibiotic therapy; however, the combination of infectious organisms, commonly viruses and bacteria, prevents a sustained protection. The severe, progressive anemia is a major challenge for treatment.

■ Prevention and Control A DNA-based carrier test was developed by the Animal Health Trust (Newmarket, United Kingdom).^1,14 The genetic test offers powerful herd management planning to avoid the mating of two carriers with the genetic defect and consequently to decrease the incidence of FIS, a fatal disease to date. The use of the genetic test has been shown to reduce the number of births of affected foals.¹⁷

Agammaglobulinemia

Melissa T. Hines

■ Definition and Etiology Agammaglobulinemia in horses is a rare primary immunodeficiency characterized by complete B-cell dysfunction with an intact cell-mediated response. The disorder is associated with a failure of B-lymphocyte maturation, absent or very low serum Ig concentrations, and failure of specific antibody production. It has been described in Thor­oughbreds, Quarter Horses, and Standardbreds, and thus far it has been reported only in males, suggesting that the trait may be X-linked.^1-4 Although this linkage has not been proven in the horse, the disorder is sometimes referred to as X-linked agammaglobulinemia.

■ Clinical Signs and Differential Diagnoses Horses with agammaglobulinemia typically develop signs around 2 to 6 months of age as transferred maternal antibodies decline. The specific signs reflect the infections that develop. Pneumonia and septic arthritis, as well as dermatitis and enteritis, have been reported. Infections often respond poorly to therapy. The differential diagnosis list should include transient hypogamma­globulinemia and common variable immunodeficiency (CVID).

■ Clinical Pathology Total peripheral blood lymphocyte counts are within the normal range, but lymphocyte phenotyp­ing reveals a lack of circulating B cells with normal numbers of T cells. Changes on routine laboratory evaluation are nonspecific and may reflect chronic infection. Depending on the response to infection, neutrophil counts may be normal, low, or high.

Serum concentrations of IgM, IgA, and all subisotypes of IgG are persistently low or absent. Depending on the age at evaluation, the assessment of antibody concentrations may be complicated by the presence of maternal antibody. Considering that the half-life of IgG is longer than that of IgM, serial sampling will demonstrate a decline in antibody concentrations, with IgM and IgA typically decreasing first, followed by a decrease in all subisotypes of IgG. In some foals, low levels of Ig may persist, possibly due to either a prolonged catabolism of antibody or some residual B-cell activity, which has been identi­fied in human patients with X-linked agammaglobulinemia.^1-5

Horses affected with agammaglobulinemia do not produce specific antibody in response to immunization regardless of the antigen. Cell-mediated responses are essentially normal, including lymphocyte proliferation in response to T-cell mitogens (PHA and PWM) and DTH skin testing by intra­dermal (ID) injection of PHA.

■ Pathophysiology The molecular basis of agammaglobu­linemia in horses is unknown, but a defect at the stem cell level that blocks early B-cell differentiation is suspected because all classes of Ig are affected. In human patients with X-linked agam­maglobulinemia, a mutation in Btk, a gene encoding Bruton's tyrosine kinase, accounts for the disease.^7,8 Assessment of the Btk gene in horses may help in understanding this disorder.

■ Necropsy Findings Gross and histologic changes in the lymph nodes, spleen, and thymus have been observed in horses with agammaglobulinemia.^1-4 Lymph nodes are small and microscopically show as being devoid of germinal centers and follicles. Grossly, the spleen may be small and contracted and microscopically shows lack of germinal centers, periarterio- lar lymphocytic sheaths, and plasma cells. The thymus may be small and difficult to locate, making it necessary in some cases to blindly sample tissue from the mediastinal region. Histologically, the thymus does not show recognizable epithelial structure and lacks defined nodules. The reason for cell-mediated functions to be normal while the architecture of the thymus is so abnormal remains unexplained.

■ Treatment and Prognosis In the absence of production of autologous antibody, affected horses develop recurrent infections. Although antimicrobial therapy and administration of plasma may temporarily control infections, the long-term prognosis is poor. In human patients with X-linked agam­maglobulinemia, early diagnosis along with well-controlled Ig replacement therapy have allowed patients to survive well into adulthood.⁹

Horses with agammaglobulinemia illustrate that T cells make a significant contribution to immunity along with B cells. Horses with defects in both B- and T-cell functions (e.g., SCID) seldom survive to 5 months of age, whereas horses with a pure B-cell defect such as agammaglobulinemia may survive between 1 and 2 years. Agammaglobulinemia with a lack of circulating B cells was identified in a Pinto gelding that did not exhibit recurrent pyogenic infections until 3 years of age.¹² It is not certain whether this horse had agammaglobulinemia or a form of common variable immunodeficiency. Although it could not be established whether the immunodeficiency was primary or secondary, an underlying disease process was not identified.