Immunodeficiency Diseases

Infectious disease, especially of long dura­tion, in an individual animal but not in other animals at similar risk is often the result of a compromised host defense system. Defects in defense mechanisms can involve the lympho­cyte, neutrophil, monocyte/macrophage and complement systems. The severity and chron-icity of the infectious disease in affected ani­mals depend on the nature of the defect. Animals with defective host defense systems often have repeated infections caused in many cases by microorganisms with little or no effect on nor­mal animals. A few defects in the equine lym­phocyte system have been described and characterized. Although the incidence of lymphoid defects in horses exceeds that in other species, it is clear from the number of unexplained recurrent infections in foals that a variety of problems have yet to be defined.

Combined Immunodeficiency

Combined immunodeficiency (CID) is a dis­ease of foals in which there is a defect in the production of functional T- and B-lympho-cytes.^{58 60} This results in an absence of antibody

formation and cell-mediated immunity. Af­fected foals are susceptible to a variety of infec­tions by viruses, bacteria, protozoa and fungi, and die from one or more of these infections before 5 months of age.⁵⁹'⁶¹

Cause: In horses, CID is transmitted as an autosomal recessive trait.⁶²"⁶⁴ Male and female foals are affected in equal numbers. Carrier mares and stallions have no detectible immu-nologic defects and are normal in appearance. Diagnosis of CID in a foal must be made with care since such a diagnosis implicates the mare and stallion as carriers of the CID trait (het-erozygotes). An incorrect diagnosis could cause obvious problems to owners of the mare and stud implicated.

Incidence: Since the first description in 1973, CID has been diagnosed in only Arabian and part-Arabian foals. The incidence of CID in full- or part-Arabian foals has been reported as 2.3%.⁶² Based upon this incidence in foals and the autosomal recessive mode of inheritance, the incidence of carrier mares and studs is es­timated as 26%. Because of the extremely high incidence, CID should be considered in the dif­ferential diagnosis of illness in any Arabian or part-Arabian foal. Foals in herds with carriers should be checked at birth for CID.

Diagnosis: Diagnosis of CID is based on a pe­ripheral blood lymphocyte count below 1000/mm³, absence of serum IgM, and histologic changes in the lymphoid organs, including thymic hypoplasia, absence of splenic germinal centers and periarteriolar lymphocytic sheaths, and absence of germinal centers or follicles in the paracortical areas. The presence of 2 of 3 of these conditions constitutes a presumptive di­agnosis; however, all 3 abnormalities should be confirmed when implicating a mare or stallion as a carrier of the CID trait.

Clinical Signs: Affected foals that receive adequate amounts of maternal immunoglobu­lin by passive transfer appear normal at birth and do not succumb to infections until they are several weeks old.^{59 61} The importance of pas­sive transfer is demonstrated by CID foals with failures.⁶⁵ Such foals develop infection imme­diately after birth and may die within a few days. Affected foals die before 5 months of age in the absence of immunotherapy.

In a group of 66 foals with CID, clinical signs caused by infections appeared from 2-60 days of age and deaths occurred from 15 days to 4.5 months of age.⁶¹ Respiratory infections were detected in 90% of the foals with CID.⁶¹ An ad-enovirus was isolated in 73% of the foals with

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respiratory infection, which was complicated by secondary bacterial bronchopneumonia. Some of these foals also had pancreatitis caused by adenovirus infection. An additional 17% had only bacterial bronchopneumonia. Al­most 40% of the foals with viral and/or bacte­rial infections also had infection by Pneumocystis carinii.

After pulmonary lesions, hepatic lesions of undetermined origin were the next most fre­quent lesions observed and accounted for death in about 10% of the cases. A severe intestinal infection was noted in one foal, which attests to the protective effect of maternal IgA in the mare's milk. Navel ill was responsible for death in only 1 of 66 foals.

Histopathologic Lesions: The primary le­sions of CID are in the lymphoid system.⁶⁶ Sec­ondary lesions vary with the type and location of infections.

The lymph nodes are smaller and firmer than normal unless draining an infected area. On histologic examination there are few lym­phocytes and no plasma cells in any part of the lymph node and no follicular or germinal cen­ter organization. The spleen is also small and macroscopic examination of a cut section re­veals prominent trabeculae that are closer to­gether than normal. As in the lymph nodes, the spleen has few lymphocytes, no plasma cells and no lymphoid organization. The T-lympho-cyte-dependent periarteriolar lymphocytic sheaths are absent, as are the B-lymphocyte-dependent follicles adjacent to the arterioles.

Thymuses from CID foals are uniformly hy-poplastic and difficult to locate at necropsy.⁶⁶ Microscopic examination confirms the hypo-plasia by the absence of thymocytes and lack of a distinct cortex and medulla. Often there are cystic spaces filled with cellular debris, sur­rounded by lymphoid cells and structures rep­resenting Hassall's corpuscles.

Immunologic Findings: The most significant finding in foals with CID is lymphopenia.⁵⁹ Normal foals have 4000 lymphocytes and rarely fewer than 2000 lymphocytes/mm³. Foals with CID have less than 1000 lymphocytes/mm³.

Serum immunoglobulin levels must be inter­preted with the foal's age in mind. Serum from affected foals that have not suckled contains no immunoglobulin in contrast to that of normal foals, which has IgM and sometimes detectible IgG. Foals with CID cannot be differentiated by immunoglobulin level measurement from normal foals after a normal passive transfer of maternal immunoglobulins because both nor mal and affected foals obtain IgM, IgG, IgA and IgG(T) from colostrum. The IgM derived from colostrum clears from the serum of CID foals in 2-5 weeks, depending on the amount received, and is never again present in affected foals. In contrast, normal foals produce IgM before birth and continuously produce IgM throughout life. ^{36 42}' ⁴⁸

Although IgA and IgG(T) are completely cleared from the serum of CID foals, IgG may be present until death. The IgG persists be­cause of the increasing half-life as serum levels decrease and because of the large amounts of IgG absorbed from colostrum. Therefore, con­sidering the influence of colostraJ immunoglob­ulins on serum immunoglobulin levels in foals with CID, it is best to test serum before the foal suckles or at least 2-3 weeks after birth. In the latter case, a retest at an older age may be nec­essary if IgM is present and there are other in­dications of CID, such as lymphopenia.

Tests for T-lymphocyte activity are generally negative and affected foals do not respond to delayed hypersensitivity skin tests.²⁶

Immunoglobulin-bearing B-Iymphocytes are absent from the blood and lymphoid organs.⁶⁰ These foals also fail to produce antibody follow­ing antigen injection and lack "natural" anti­body to heterologous RBC present in normal serum.⁶⁰ These conditions suggest an absence of B-lymphocyte function.

Lymphocytes appear to be the only WBC type affected in CID foals since no defects have been demonstrated in the monocytes, RBC or neutrophils.⁶⁸ The complement system also seems to be functionally intact.⁶⁰

From all the evidence, foals with CID are un­able to produce immunocompetent T- and B-lymphocytes.

Treatment: Treatment of CID is not practical since all offspring from affected mares or stal­lions are carriers. Limited success at reconsti­tuting T- and B-lymphocyte function in a foal with CID has been obtained by giving 80-day fetal liver cells iv and implanting an entire fe­tal thymus sc⁶⁷ This foal survived 11.5 months and died of causes unrelated to infection. More studies are needed to determine predictable methods of immunotherapy for affected foals.

Treated foals must be kept alive for 2-3 months after transplantaton to evaluate recon-stitution experiments. This maintenance is di­rected toward prevention and control of secondary infections. The most important as­pect is the control of respiratory infections, which is best achieved by twice weekly iv ad-

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ministraton of plasma taken from a horse hy-perimmunized with equine adenovirus.⁶¹ Bacterial infections are treated with the appro­priate antibiotics and Pneumocystis carinii in­fections are prevented by administration of potentiated sulfonamides.

Selective IgM Deficiency

Since the first recognized case of selective IgM deficiency, the disease has been diagnosed in 19 horses (13 Arabians, 4 Quarter Horses, 1 Thoroughbred, 1 Paso Fine).^{69 - 71} Selective IgM deficiency in children is inherited or can occur secondary to other problems. Whether selec­tive IgM deficiency in foals is inherited or caused by other factors is unknown. The inci­dence is also unknown, although among Ara­bian foals it is clearly less than CID.

Diagnosis is based on no or very low levels of serum IgM. Other functions of the immune sys­tem appear normal.⁷⁰

Affected foals have recurrent, low-grade re­spiratory infections and usually die by 4-8 months of age. Some have lived to 2 years of age but grew poorly.

Agammaglobulinemia

Agammaglobulinemia was diagnosed in a 1-year-old Thoroughbred.⁹⁷² The animal sur­vived to 17 months of age and lacked B-Iym-phocyte function; T-lymphocyte function was normal. Absence of B-lymphocyte function was demonstrated by lack of antibody production after injection of antigens and lack of serum IgM, IgA and IgG(T), with only small amounts of serum IgG. Histologically there was an ab­sence of plasma cells and germinal centers. The T-lymphocytes were present as deter­mined by delayed hypersensitivity skin tests.

A second case of agammaglobulinemia has been diagnosed in a male Standardbred.⁷³ One form of agammaglobulinemia in children is sex-linked and, since both affected horses were males, it is possible that equine agammaglob­ulinemia has a sex-linked mode of inheritance. However, the cause of agammaglobulinemia in horses has not been determined.

Other Immunodeficiencies

Transient hypogammaglobulinemia in an Arabian foal has been described.⁴⁸ This foal had low serum IgG and IgG(T) levels at 2 months of age; detectible immunoglobulin pro­duction did not occur until 3 months of age. All other immunologic parameters were normal. However, the foal had severe adenoviral and ministraton of plasma taken from a horse hy-perimmunized with equine adenovirus.⁶¹ Bacterial infections are treated with the appro­priate antibiotics and Pneumocystis carinii in­fections are prevented by administration of potentiated sulfonamides.

Selective IgM Deficiency

Since the first recognized case of selective IgM deficiency, the disease has been diagnosed in 19 horses (13 Arabians, 4 Quarter Horses, 1 Thoroughbred, 1 Paso Fine).^{69 - 71} Selective IgM deficiency in children is inherited or can occur secondary to other problems. Whether selec­tive IgM deficiency in foals is inherited or caused by other factors is unknown. The inci­dence is also unknown, although among Ara­bian foals it is clearly less than CID.

Diagnosis is based on no or very low levels of serum IgM. Other functions of the immune sys­tem appear normal.⁷⁰

Affected foals have recurrent, low-grade re­spiratory infections and usually die by 4-8 months of age. Some have lived to 2 years of age but grew poorly.

Agammaglobulinemia

Agammaglobulinemia was diagnosed in a 1-year-old Thoroughbred.⁹⁷² The animal sur­vived to 17 months of age and lacked B-Iym-phocyte function; T-lymphocyte function was normal. Absence of B-lymphocyte function was demonstrated by lack of antibody production after injection of antigens and lack of serum IgM, IgA and IgG(T), with only small amounts of serum IgG. Histologically there was an ab­sence of plasma cells and germinal centers. The T-lymphocytes were present as deter­mined by delayed hypersensitivity skin tests.

A second case of agammaglobulinemia has been diagnosed in a male Standardbred.⁷³ One form of agammaglobulinemia in children is sex-linked and, since both affected horses were males, it is possible that equine agammaglob­ulinemia has a sex-linked mode of inheritance. However, the cause of agammaglobulinemia in horses has not been determined.

Other Immunodeficiencies

Transient hypogammaglobulinemia in an Arabian foal has been described.⁴⁸ This foal had low serum IgG and IgG(T) levels at 2 months of age; detectible immunoglobulin pro­duction did not occur until 3 months of age. All other immunologic parameters were normal. However, the foal had severe adenoviral and bacterial infections during the period of hypo-gammaglobu linemia.

Many foals with infections do not have ab­normal immunoglobulin levels or lymphocyte numbers and do not fit into the categories de­scribed in this chapter. Since most laboratories screen cases by measuring immunoglobulins and counting lymphocytes, foals with defects in the T-lymphocyte system but normal B-lympho­cyte function are probably missed. Reliable tests for measuring equine T-lymphocyte function are needed to augment skin testing.