Vet Clin Equine 24 (2008) 299–310

Immunodeficiency Disorders in Horses

Mark V. Crisman, DVM, MS*, W. Kent Scarratt, DVM
Department of Large Animal Clinical Sciences, Virginia Maryland Regional College
of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061, USA

Immunodeficiencies are characterized as primary (genetic) or secondary

(acquired). Primary immunodeficiencies are relatively uncommon; however,
clinically, they present a significant challenge to the practitioner, especially if
the underlying disorder goes unrecognized. Secondary immunodeficiencies
may present at any age, but failure of passive transfer (FPT) in neonatal
foals is most commonly encountered. This article provides a general over-
view of clinical signs and diagnosis of primary and secondary immunodefi-
ciencies currently recognized in horses.

Immunodeficiencies
Immunodeficiency is generally defined as a state in which the immune sys-
tem’s ability to ward off infectious disease is compromised or entirely ab-
sent. Cells of the immune system are derived from hematopoietic stem
cells within the bone marrow that comprise common lymphoid precursor
cells. Under the influence of the thymus or the equine equivalent of the
bursa of Fabricius, progeny of the precursor cells differentiate further into
T and B lymphocytes, respectively. In the normal equine fetus, functional
T lymphocytes are present at 100 days of gestation and functional B
lymphocytes are present by 200 days. This suggests that normal foals are im-
munocompetent at birth [1]. Specific immunologic responses arise from
a well-orchestrated complex interaction among the various populations of
lymphoid cells. The immune response is activated when monocytoid cells
present antigen to lymphocytes and, under the influence of T cells, elaborate
helping and suppressing signals. Helper T cells (CD4+) are divided
further in distinct subsets based on cytokine profiles. TH1 cells produce
two cytokines (interferon gamma [INF-g] and IL-2), which help initiate

* Corresponding author.
E-mail address: farmuse@vt.edu (M.V. Crisman).

0749-0739/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.cveq.2008.03.003 vetequine.theclinics.com
300 CRISMAN & SCARRATT

the sell-mediated immune response. TH2 cells produce IL-4, IL-5, and IL-
13, which influence B-cell differentiation into class-specific immunoglobu-
lin-producing cells. Many of the recognized immunodeficiency syndromes
can be attributed to a cellular (genetic) defect at one of these levels of lym-
phoid differentiation, including the primary immunodeficiencies. Alterna-
tively, secondary immunodeficiency disorders generally result from FPT
of maternal antibody, malnutrition, neoplasia, or treatment with immuno-
suppressive drugs.
Immunodeficiencies (primary or secondary) clearly increase the risk for
infections; typically, this is the reason why these horses are presented for
medical attention. If the underlying immune defect is unrecognized, horses
may ultimately succumb to repeated infections and death. Many of the sec-
ondary immunodeficiencies, specifically FPT, are well characterized, easily
recognized, and generally respond to therapeutic intervention. Conversely,
primary immunodeficiencies are more challenging to recognize and difficult,
if not impossible, to treat. Clearly, early recognition of these immune disor-
ders is essential for successful resolution of the case. If the clinician’s initial
therapeutic intervention is unsuccessful or the patient’s history suggests an
underlying immune defect (ie, chronic infections, failure to thrive), the diag-
nostic exercise should be expanded to investigate the immune system. The
specific defect in the immune system determines the clinical signs associated
with the disorder. Several hallmark features are commonly associated with
immunodeficiencies, however, including the following: (1) recurrent or per-
sistent infections, (2) inadequate response to standard therapeutic interven-
tion, (3) susceptibility to infection by low-grade pathogens, (4) failure to
respond to immunization, (5) failure to thrive or gain weight and grow
normally, (6) familial history of an immune deficiency, and (7) onset of
infections within the first few weeks to months of life [2].
Immunodeficiencies are frequently characterized according to the specific
components of the dysfunctional immune system.
Humoral immunodeficiencies involve impairment of B-cell development
and maturation (failure to express specific classes of immunoglobulin on
the cell surface) and failure to respond to T helper (Th)–cell signals. The
resultant expression of selected immunoglobulin isotypes may be absent
or decreased. Clinically, affected horses experience recurrent infections
from opportunistic organisms (eg, Streptococcus, Staphylococcus, Crypto-
sporidia) and may present with pneumonia, sinusitis, dermatitis, or a general
failure to thrive. Several disorders involving humoral deficiencies have been
described in horses, including common variable immunodeficiency, Fell
pony syndrome, and selective immunoglobulin M (IgM) deficiency.
Cellular immunodeficiencies include T-cell disorders that may directly
affect cytotoxic T-cell function or indirectly affect B-cell function through
lack of T-cell signaling. Affected foals commonly fail to mount competent cel-
lular immune responses against intracellular pathogens, such as Rhodococcus
equi and rotavirus. A recent study demonstrated that Th1 immune responses,
 IMMUNODEFICIENCY DISORDERS IN HORSES 301

characterized by production of interferon-g (IFNg), are deficient in normal

neonatal foals and that this may contribute to their susceptibility to intracel-
lular pathogens [3]. Th1 cytokines, such as IFNg, are pivotal for the induction
of antigen-specific cellular immune responses and specifically for an immune
response to R equi infection. In general, cellular immune disorders are associ-
ated with infections of intracellular pathogens (viruses, protozoa, and myco-
bacteria) and are usually seen in neonatal foals. Cellular immune deficiencies
are rarely described in adult horses. Combined immunodeficiencies include
B-cell (humoral) and T-cell (cellular) dysfunction and, with rare exception,
are fatal in horses. The prototypical combined immunodeficiency in horses
is severe combined immunodeficiency (SCID) in Arabian foals.
This review considers our current understanding of, and the salient fea-
tures associated with, primary and secondary immunodeficiencies in horses
and focuses on the diagnosis and effective management of these conditions.
The ontogeny and specific constituents of the immune system have been
reviewed previously [2,4].

Primary immunodeficiencies
Primary immunodeficiency disorders generally arise from a defect in the
immune system and most frequently have a genetic basis. Several primary
immunodeficiencies have been recognized in horses, including SCID, selec-
tive IgM deficiency, agammaglobulinemia, and Fell pony immunodeficiency
syndrome.

Severe combined immunodeficiency

SCID is a genetic disorder described in Arabian foals, human beings,
mice, and dogs. It is characterized by a lack of functional B and T lympho-
cytes [5]. Affected individuals are completely incapable of mounting any
antigen-specific immune responses. SCID was first described in an Arabian
foal in 1973 and has subsequently been identified in the United States, Aus-
tralia, Canada, and the United Kingdom [2,6]. In Arabian horses, SCID is
inherited as an autosomal recessive trait [7]. On a molecular level, SCID
results from a mutation encoding for the catalytic subunit of the enzyme
DNA-dependent protein kinase (DNA-PK). This enzyme is essential for
gene rearrangement that ultimately encodes the antigen-receptor complex
on the cell surface of B and T lymphocytes. Absence of DNA-PK results
in the elimination of lymphocyte precursors, and affected foals are born
without functional B and T lymphocytes [8].

Clinical presentation
Arabian foals that have SCID are generally normal at birth and may not
demonstrate clinical signs for weeks to months depending on the extent and
quality of passive transfer and hostility of the environment (exposure to
302 CRISMAN & SCARRATT

pathogens). As maternally derived antibody wanes, foals that have SCID

are susceptible to a host of bacterial, viral, fungal, and protozoal agents.
The respiratory tract and, to a lesser extent, gastrointestinal tract are the
first systems affected. Common causative agents include adenovirus, which
was identified in approximately two thirds of foals that had SCID in one
study [9], R equi, Pneumocystis, and Cryptosporidium. Initially, foals that
have SCID may respond to antimicrobial therapy; however, infections recur
and affected foals eventually succumb within a few months of age.

Diagnosis
Definitive diagnosis of SCID in Arabian foals is accomplished by genetic
testing (VetGen, Ann Arbor, Michigan). DNA is isolated from blood
or cheek swabs and amplified by polymerase chain reaction (PCR) and
hybridized with specific probes for normal and mutant gene sequences
[10]. Clinically, an Arabian foal presenting at 1 or 2 months of age with
chronic infections from low-grade pathogens, severe persistent lymphopenia
(!1.0  109/L) and an absence of serum IgM, as measured by single radial
immunodiffusion (SRID), is certainly suspect. If these criteria are observed,
the DNA-based test should be performed. The molecular-based diagnosis is
definitive and greatly expedites the time and expense associated with these
cases for which there is no satisfactory treatment. Additionally, the DNA-
based test greatly facilitates responsible breeding practices. Mares and stal-
lions intended for breeding should be tested to ensure that they are free of
the SCID gene (homozygous normal). If a heterozygous individual is se-
lected for breeding, it should be bred only to a homozygous normal mate.

Selective immunoglobulin M deficiency

After presentation of a foreign antigen, IgM is the initial immunoglobulin
produced before isotype switching occurs. Serum IgM accounts for approx-
imately 10% of the total serum immunoglobulin. Selective IgM deficiencies
have been reported in foals [11,12] and adult horses [13–18]. IgM deficiency
has also been observed in some horses with neoplasia, and the spontaneous
recovery observed in others suggests that this deficiency may represent
a primary or secondary disorder. To meet the criteria for selective IgM
deficiency, serum IgM concentrations must be greater than 2 SD less than
age-matched horses and all other immunoglobulin classes (IgG, IgA, and
IgG subtype T [IgG(T)]) must be within reference intervals. Blood lympho-
cyte counts and responses are normal in these individuals. Selective IgM
deficiency has been observed in several breeds of horse, although Arabians
and quarter horses are most frequently reported [12,19].

Clinical presentation
Two different clinical presentations occur. The first and most common
presentation represents a primary immunodeficiency and involves foals
 IMMUNODEFICIENCY DISORDERS IN HORSES 303

between 2 and 8 months of age (usually 2–3 months of age). These foals are
generally small for their age and have repeated microbial infections. Gram-
negative bacteria (Klebsiella spp) are common causative organisms. After
aggressive antimicrobial therapy, IgM-deficient foals improve only to re-
lapse several weeks later. The respiratory tract is most frequently involved,
and most of these foals die by 8 months of age. Interestingly, foals that do
survive often have IgM concentrations between 1 and 1.5 SD less than age-
matched controls and may fall into the ‘‘failure to thrive’’ category.
The second presentation involves adult horses (O2 years of age). Some
reports suggest an association between selective IgM deficiency and lym-
phoreticular neoplasms [13,17]. A recent report recognized that IgM defi-
ciency may be identified in conditions other than lymphoma, however
[20]. The latter study reported that the sensitivity and specificity of serum
IgM concentrations less than 0.6 g/L for detecting equine lymphoma were
50% and 35%, respectively. At a cutoff point of less than 0.23 g/L, the sen-
sitivity remained low (28%) but the specificity improved to 88% [20]. Thus,
IgM values should not be used as a screening test for equine lymphoma.

Diagnosis
Diagnosis of selective IgM deficiency is made by determination of serum
IgM concentrations using SRID. Reference intervals for IgM concentra-
tions in adult horses are 1.2  0.3 g/L, suggesting that IgM concentrations
less than 0.6 g/L be considered IgM deficient (!2 SD lower than age-
matched controls). A recent study suggests that this cutoff be adjusted to
less than 0.23 g/L, because a significant population of the horses analyzed
(5 of 24 ‘‘normal’’ fit horses) were determined to be at lower than the higher
cutoff value [20]. In foals from 4 to 8 months of age, IgM concentrations less
than 0.15 g/L are suggestive of a selective IgM deficiency if coupled with
concentrations of other immunoglobulin classes within reference limits.

Management
Horses diagnosed with selective IgM deficiency are difficult to manage.
There is no specific treatment to address the deficiency. Foals diagnosed
with a primary selective IgM deficiency have a guarded prognosis at best.
Plasma transfusions and aggressive antimicrobial therapy may temporarily
control infections.
In a retrospective study of older horses (older than 1 year of age) without
lymphoma and with IgM concentrations less than 0.6 g/L, 13 (59%) of
22 were reported to be healthy at 1 year after discharge from the hospital [20].

Fell pony immunodeficiency syndrome

In the late 1990s, a syndrome of severe anemia, immunodeficiency, and
peripheral ganglionopathy was described in Fell pony foals [21]. Evidence
suggests that Fell pony syndrome is a genetic disease inherited as an
304 CRISMAN & SCARRATT

autosomal recessive trait, although the molecular basis for the disorder is
undefined.

Clinical presentation
Affected foals seem to be normal at birth, but clinical signs, including ill
thrift, anemia, diarrhea, cough, and failure to suckle, appear within 2 to
3 weeks. Anemia can be severe, with small numbers of erythroid precursors
in the bone marrow. In some foals, adenoviral bronchopneumonia, crypto-
sporidial enteritis, and pancreatitis have been identified at necropsy [21].
Lingual hyperkeratosis, along with frequent ‘‘chewing’’ movements, has
also been noted. Affected foals typically die by 3 months of age.

Diagnosis
Severe anemia is a consistent clinical feature. Total immunoglobulin con-
centrations are initially within reference limits, depending on passive trans-
fer of maternal antibody. Affected foals lack the ability to synthesize IgM
and IgG isotypes, including IgGa and IgGb [22]. Additionally, a marked
deficiency of B lymphocytes has been observed on immunohistochemical
analysis of lymph nodes and thymus. Pathologic findings include a small
thymus, with no secondary lymphoid follicles or plasma cells. Neuronal
chromatolysis, involving trigeminal, cranial mesenteric, and peripheral
nerve ganglia, is found at necropsy. Typically, a diagnosis is made on the
presence of clinical signs in a Fell pony, along with histologic confirmation
of bone marrow erythroid hypoplasia.

Management and prognosis

Antimicrobial therapy and supportive care of specific infections are of
limited efficacy in affected foals, especially those presenting with diarrhea
and severe anemia. Most foals die by 3 months of age despite aggressive
treatment [21].

Other immunodeficiency syndromes

Other rare primary immunodeficiency disorders have been reported in
foals. The pathogenesis and genetic basis of these disorders are poorly de-
fined or unknown. Transient hypogammaglobulinemia has been reported
in an Arabian foal and a thoroughbred foal [19]. The numbers of B and
T lymphocytes were within reference limits, but onset of immunoglobulin
synthesis was delayed. Clinical signs were consistent with bacterial and viral
infections observed at the time of waning passive immunity. Laboratory
parameters suggested chronic infection, with low serum IgG (!2 g/L)
and IgG(T) (!0.2 g/L) at 2 to 4 months of age and marginal IgM
(O0.15 g/L) and IgA (O0.2 g/L). Aggressive antimicrobial therapy and
plasma transfusions were essential to control infections. Spontaneous recov-
ery was observed in one foal at 185 days of age [23].
 IMMUNODEFICIENCY DISORDERS IN HORSES 305

Agammaglobulinemia has been described in five colts of thoroughbred,

standardbred, and quarter horse breeding. The fact that all cases have
been described in male horses suggests (but does not prove) that agamma-
globulinemia may be an X-linked disorder. The disorder is characterized
by a complete absence of B lymphocytes and subsequent failure to produce
immunoglobulins [24]. Clinically, foals were between 2 and 6 months of age
and demonstrated multisystemic disease, involving the respiratory, diges-
tive, and musculoskeletal systems as maternal antibody decreased. No sero-
logic response occurs after immunization. As observed with other primary
immunodeficiencies, affected horses initially respond to therapy, but infec-
tions recur and horses die between 1 and 2 years of age. Horses with agam-
maglobulinemia have no detectable serum IgM and IgA concentrations,
along with extremely low serum concentrations of IgG and IgG(T) that
decline over time depending on the level of passive immunity. Total blood
lymphocyte counts are within reference limits, but lymphocyte phenotyping
reveals a complete absence of B lymphocytes.

Secondary immunodeficiencies
Failure of passive transfer
The most common immunodeficiency disorder in the horse is FPT of
colostral immunity [4,25–27]. FPT has been defined as failure of the foal
to ingest or absorb adequate immunoglobulin from colostrum [27]. The
causes of FPT in the foal include the following: (1) failure of the foal to in-
gest an adequate volume of colostrum early in the postnatal period, (2) loss
of colostrum by premature lactation, (3) inadequate immunoglobulin con-
centration of colostrum, and (4) insufficient absorption of immunoglobulin
by the foal’s intestinal tract [26,28,29]. FPT is the most important risk factor
for the development of infection and death during the first month of life
[26,27]. The incidence of FPT in foals has been estimated to range between
3% and 24% [4,26–28,30].

Diagnosis of failure of passive transfer of immunity

The diagnosis of FPT is based on the serum concentration of IgG at 18 to
24 hours of age. Most equine veterinarians consider adequate passive trans-
fer of immunity in 1-day-old foals to be a serum concentration of IgG
greater than 8 g/L, because this concentration is associated with a signifi-
cantly higher rate of survival [4,26,27,29]. Many foals with a serum concen-
tration of IgG between 4 and 8 g/L remain healthy, however, if they are
raised in a clean environment [4,26].
The most quantitatively accurate test available for the diagnosis of FPT is
the radial immunodiffusion (RID) test (VMRD, Pullman, Washington;
Plasvacc USA, Templeton, California) [25–28]. The RID test is based on
306 CRISMAN & SCARRATT

the ability of antigen and antibody to precipitate at equivalence when com-

bined in proportions on agar gel plates. The disadvantages of the RID test
are the cost, technical skills, and time (24 hours) required to perform the test
[25–28,30,31]. Although the RID test is accurate for the diagnosis of FPT, it
is an impractical test for the diagnosis of FPT in a sick foal when a rapid
diagnosis and treatment are required.
A variety of rapid screening tests are available for the estimation of IgG.
Criteria for selecting a screening test include accuracy, time required to per-
form the test, ease of performance, and cost [4,25–27,32]. Most screening
tests are accurate in identifying foals that have complete FPT (IgG !2
g/L); however, there is substantial variation in the ability of these tests to
detect foals that have partial FPT (IgG 2–8 g/L). Questionable results of
a rapid screening test for FPT should be confirmed with the RID test
[27]. Rapid screening tests available for the estimation of IgG and diagnosis
of FPT in the foal include measurement of total serum protein (TSP) con-
centration, the zinc sulfate turbidity test, the glutaraldehyde coagulation
test, the latex agglutination test, and enzyme immunoassay [26–28,32,33].
Estimation of total protein in serum by refractometry is a rapid, inexpen-
sive, and accurate test for the diagnosis of FPT in the calf [33]. Determina-
tion of the TSP concentration is an unreliable test for the diagnosis of FPT
in the foal because of the wide range of values in neonatal foals [32,33]. Re-
sults of a study that compared the TSP measured by refractometry with the
RID test revealed that a foal with a TSP less than 45 g/L was likely to have
a serum concentration of IgG less than 4 g/L, whereas a foal with a TSP
greater than 60 g/L was unlikely to have a serum IgG concentration less
than 8 g/L [32]. The results of another study in foals that compared the con-
centrations of TSP and serum globulin measured by an automated clinical
chemistry analyzer with the results of the RID test revealed that the concen-
trations of TSP and serum globulin were poor indicators of FPT [33].
The zinc sulfate turbidity test (Equi Z, Equine FPT Test Kit; VMRD) is
based on the precipitation of IgG when serum is added to a solution of zinc
sulfate. The degree of turbidity is usually proportional to the concentration
of IgG. Turbidity may be increased by hemolysis, however, and influenced
by poor operating conditions and poor-quality reagents [25,26,28,31]. A cor-
rection factor was useful for the interpretation of results of the zinc sulfate
turbidity test when hemolyzed serum was used [34].
The glutaraldehyde coagulation test (Gamma-Check-E; Plasvacc USA) is
based on the coagulation of IgG when serum is added to a solution of
glutaraldehyde. The formation of a gel in 10 minutes indicates a serum
IgG concentration of greater than 8 g/L, whereas formation of a gel in
60 minutes indicates a serum IgG concentration of greater than 4 g/L. He-
molysis in the serum sample may overestimate the concentration of IgG
[25,26,28,31].The results of a study that compared the glutaraldehyde coag-
ulation test with the RID test in neonatal foals revealed that the sensitivity
and specificity of the glutaraldehyde coagulation test for IgG less than 8 g/L
 IMMUNODEFICIENCY DISORDERS IN HORSES 307

were 100% and 59%, respectively, and that they were 95% and 80%, respec-
tively, for IgG less than 4 g/L [35]. The poor specificity of the glutaraldehyde
coagulation test for detecting serum concentrations of IgG less than 8 g/L
suggests that a foal that has adequate passive transfer may be diagnosed
with FPT based on the glutaraldehyde coagulation test.
The latex agglutination test (Foalcheck, Centaur, Overland Park, Kan-
sas) is based on macroscopic agglutination when immunoglobulin in serum
is mixed with an anti-equine IgG absorbed on latex particles. The amount of
agglutination is proportional to the serum concentration of IgG. The results
of a study that compared the latex agglutination test with the RID test in
neonatal foals revealed that the sensitivity and specificity of the latex agglu-
tination test for IgG less than 8 g/L were 72% and 79%, respectively, and
that they were 53% and 79%, respectively, for IgG less than 4 g/L [35].
The investigators concluded that the poor sensitivity of the latex agglutina-
tion test made it an inappropriate screening test for FPT in foals.
A variety of quantitative (DVM Stat; Veterinary Diagnostics, Belgium,
Wisconsin) and semiquantitative (Whole Blood Foal IgG Test Kits; Mid-
land Bioproducts, Boone, Iowa) enzyme immunoassays are available for
the diagnosis of FPT in the foal [4,33]. A convenient membrane filter–based
ELISA system (SNAP Foal Test; Idexx, Westbrook, Maine) can be per-
formed on-site with serum, plasma, or whole blood [25]. A study that com-
pared the results of the SNAP test with the RID test in neonatal foals found
that the results were similar in 64% of the samples. The best results were
found with low (!4 g/L) and high (O8 g/L) concentrations of IgG, with
accuracy rates of 80% and 89%, respectively [29]. Another study that com-
pared the results of the SNAP test with those of the RID test in neonatal
foals revealed that the sensitivities of the SNAP test to detect serum IgG
concentrations less than 4 g/L and less than 8 g/L were 90% and 95%, re-
spectively, whereas the specificities were 79% and 52%, respectively. These
investigators determined that the specificity of the SNAP test for an IgG
concentration less than 8 g/L was significantly lower in foals that had bac-
teremia. The low specificity of the SNAP test suggests that many sick foals
with adequate passive transfer of immunity may potentially be diagnosed as
having FPT with the SNAP test [32].
A turbidimetric immunoassay (TIA) for the detection of serum IgG is
based on the immunologic agglutination and subsequent scattering of light
by the agglutination products when IgG in serum (antigen) is mixed with
goat anti-equine IgG (antibody). The resultant turbidity is proportional to
the IgG concentration [31]. An automated TIA can be performed on a routine
clinical chemistry analyzer. Advantages of the automated TIA compared
with the RID test include elimination of human error in the measurement
of the precipitin ring diameters and a much shorter turnaround time. The re-
sults of a study that compared the results of an automated TIA with the RID
test in neonatal foals revealed that the sensitivity and specificity of the TIA
for IgG less than 8 g/L were 81% and 86%, respectively, and that they
308 CRISMAN & SCARRATT

were 63% and 92%, respectively for IgG less than 4 g/L. The investigators
concluded that a significant linear relation was found between IgG concen-
trations determined by the TIA and RID [31].
Infrared (IR) spectroscopy is a relatively new technique for the character-
ization of biologic molecules in fluids [30]. IR radiation is transmitted
through the sample, and the IR spectrometer records the wavelength depen-
dence of radiation absorption by the sample. A study that compared the
serum concentration of IgG determined by IR spectroscopy and the RID
test revealed high specificity (93%), sensitivity (97%), and accuracy (96%)
of the IR spectroscopy technique [30].

Treatment of failure of passive transfer of immunity

The treatment of the foal that has FPT depends on the age of the foal at
the time of diagnosis and any clinical signs or hematologic evidence of sep-
ticemia. Colostrum should be administered by a nipple bottle or nasogastric
tube if a foal is less than 12 hours old and FPT is suspected because of pre-
mature lactation, poor-quality or insufficient colostrum, or neonatal weak-
ness. If the foal is older than 12 hours of age and FPT is suspected or
confirmed, the foal should receive a plasma transfusion [4,26,27]. Plasma is
available commercially from a variety of sources (Lake Immunogenics, On-
tario, New York; Plasvacc USA). If the foal has suspected or confirmed FPT
and septicemia based on the results of clinical or hematologic examination,
the foal should also be treated with a broad-spectrum antimicrobial drug.

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