The relationship between ovine lymphocyte antigens and parasitological and production parameters in romney sheep

THE RlELATIONSHIP BETWEEN OVINE LYMPHOCYTE ANTIGENS AND PARASITOLOGICAL AND PRODUCTION PARAMETERS IN ROh4NEY SHEEP P. G. C. DOUCH’ and P. M. OUTTERIDGE~ *Wallaceville Animal Research Centre, MAFTech, Ministry of Agriculture and Fisheries, P.O. Box 40063, Upper Hutt, New Zealand tCSIR0, Division of Animal Health, McMaster Laboratory, Private Bag No. 1, P.O. Glebe, NSW 2037, Australia (Received 5 January 1988; accepted 18 August 1988) Abstract-DoucH P. G. C. and OUTTERIDGE P. M. 1989. The relationship between ovine Iymphocyte antigens and p~asitoIo~c~ and production parameters in Romney sheep. lnternationalfournaZ~o~~urasirology 19: 35-41. The occurrence of ovine lymphocyte antigen (OLA) types in two flocks of New Zealand Romney sheep was examined in relation to resistance to nematode parasites [as judged by faecal egg counts (FEC)], plasma pepsinogen levels, liveweight and weight gains. A panel of OLA-typing antisera (SY l-16) which determine class 1 MHC antigens of the sheep was used. The OLA combination SY la + lb was found exclusively in Romney sheep of both flocks having below average FEC, but was present in low frequency (5%). In one flock, sheep possessing this antigen combination had consistently lower FEC from weaning to 1 year of age than sheep without this combination. SY 6 occurred significantly more frequently in above average FEC sheep and was associated with significantly higher FEC during secondary ch~eng~i~~tion. Plaska pepsinogeh levels were significantly lower in those sheep possessingSY 2 or Sy 3 but these OLA tvoes were not associated with lower than average FEC. No OLA type was associated with above average weiihht gain but in one flock sheep with SY lb and>Y la + lb had si&ficantly lower weight gains between weaning and 6 months of age than sheep without these OLA types. A similar association was not found in the other flock. Sheep in one flock with SY 16 were significantly heavier than those without this antigen. No other associations between OLA types and liveweight were found. INDEX KEY WORDS: Ovine lymphocyte antigen; OLA; Romney; nematode resistance; liveweight; weight gain; selective breeding; Trichostrongyluscolubriformis.

applied as predictive genetic markers for the selection of nematode resistance to resilience in Romney sheep as has been indicated previously in Merinos.

THE ovine lymphocyte antigen (OLA) SY 1 had previously been reported to be associated with the response of Merino sheep to vaccination against the nematode parasite Trichostrongvlus colubriformis (Outteridge, Windon & Din&en, 1985). More recent observations suggest the SY 1 antigen comprises two alleles, SY la and SY lb, at the same locus and that possession of both is associated with greater responsiveness to vacc~ation against T. colubrifo~~ than possession of either type alone (Outteridge, Windon, Dineen & Smith, 1986). Furthermore, in the same study, the presence of SY 2 in addition to both SY la and SY lb appeared to be associated with greater resistance to infection than SY la plus SY 1b. It has been suggested that OLA type could be of practical value as a genetic marker in selecting sheep for increased resistance to nematodes (Outteridge et al., 1985; Luffau, Nguyen, Cullen, Vu Tien Khang, Bouix & Ricordeau, 1986). This paper examines the OLA types in two flocks of New Zealand Romney sheep, in which both parasite and production parameters were also monitored, in order to explore the possibility that OLA could be

MATERIALS AND METHODS Sheep. Romney sheep were reared and maintained on pasture at the Kaitoke farm of the Wallaceville Animal Research Centre. Flock 1 comprised 17 ram lambs and 181 ewe lambs born during September 1984. The ram lambs had been selected on the basis of parasitolo~c~ and pr~uctivity criteria from a flock of 146 ram lambs which was maintained from birth on pasture. The ram lambs received no anthelmintic treatment. The ewe lambs were also maintained on pasture and their management was divided into three phases during each of which sheep were exposed to natural infection by parasites. Phase 1 covered the period between birth of the lambs and the first time they were drenched, 7 March 1985 (Table 1). Phase 2 covered a subsequent 3 month period during which two further drenches were given at 28 day intervals (4 April; 2 May) and in which faecal egg count (FEC) regain was monitored 28 days after each drench. Phase 3 overlapped Phase 2 for 28 days and covered the period between 2 May and 30 August during which FEC regain was monitored. Thereafter, the flock was used for other studies. Flock 2 is a closed flock having been derived from 50 ewes mated with randomly selected rams in 1978 35

36

P. G. C. DOUCH and P. M. OUTTERIDGE

TABLE I-PAXASITOLOGICALOBSERVATIONS OFFLOCK1 EWE

LAMBS,5.12.1984-30.8.198.5 Flock mean (FEC) (epg)

Period Phase 1 5 December-7

March

1922 (422-4667)

Phase 2

7 March?-4 April 4 Aprilt-2 May 2 May?-30 May

630 (O-61 00) 219 (0-3400) 106 (o-3800)

Phase 3 2 May+30 August

238 (O-6425)

tAnthelmintic treatment. Ranges for FEC shown in parentheses. and comprised 97 mixed age females and 37 mixed age males. Certain animals were subsequently selected for breeding on the basis of high bodyweight or high growth rate under parasite chalfenge in the absence of ~thel~ntic treatment. (In some years of high nematode availability a ‘salvage’ drench was used to minimize deaths.) Merino sheep examined for OLA type (Outteridge, unpublished data) comprised 820 animals of mixed age and sex drawn from seven flocks in New South Wales (n = 526), seven flocks in Victoria (n = 261) and two flocks in Queensland (n = 33). Paras~toi~g~cal techniques nnd selection criteria. Sheep were monitored for FEC, using the modified McMaster method, at fort~ghdy or monthly intervals from weaning (December). The oarasites contributine to the FEC were predomin&tly Trikhostrongylus spp. and Ostertagia circumcincta, but differential counts were not carried out routinely. Flock 1 ewe lambs were assigned to either a high egg count (HEC) group (n = 86) or a low egg count @Ed? group (n = 95) on the basis of having individual mean FEC during Phase 1 (Table 1) above or below the flock mean FEC for this period (mean HEC 2624 epg, range 1922-4667; mean LEC 1235 epg, range 422-1911). The FEC 28 days after drench treatment is also given in Table 1. Selected Flock 1 ram lambs had the following FEC; HEC mean 11,180 epg, range 6733-17,133 (n = 7); LEC mean 2587 epg, range 1633-3900 (n = 10). Flock 2 sheep were assigned to similar groups on the basis of above or below flock mean FEC in the aeriod December-April of their first year in order to ovekme di~cuIties in’selection on FEC alone which showed considerable between-year variation. Plasma pepsinogen

levels and production

parameters.

Blood samples were taken from sheep of Flock 1 at monthly intervals and pepsinogen levels determined using the Korot’ko & lslyamova (1963) modification of Hirschowitz’s (1955) method. Flock 1 sheep were weighed at monthly intervals and weight gains for each phase determined. The interrelationships of these parameters and FEC are the subject of a separate report (Bissett, Brunsdon, Douch & Vlassoff, in preparation). Lympho~yre*preparabon and typing. Lymphocytes were nrcnared from blood usina Ficoll-Paque pharmacia, South Sea’s Ltd.), and the ~~r~~ytoto~~i~y test carried out as described previously (Outteridge, et al., 1985). The temperature of the reaction between lymphocyte, alloantisera and compiement was maintained at 22°C in an incubator. An extended panel of OLA-typing antisera (SY 1-16) was used and this included types S 12, 13, 14, 15 and 16 which

have been characterized since the previous reports (Outteridge et al., 1985, 1986). All these types appeared to be independent alleles of class I MHC antigens of the sheep but they have not yet been ascribed to genetic loci. Typing panels contained at least four antisera for each specificity. The correlation coefficients were, for example, with SY la between 0.67 and 0.86 for the Merino sheep. Antisera prepared from Merino sheep have previously been shown to efficiently type other breeds (Spooner, Teale & Cullen, 1988) and in the present study correlation coefficients greater than 0.7 found for the common types SY la, lb, 6, 12-15 for the Romney sheep suggest that these antisera also type this breed without loss of efficiency. Statistical analysis. One-way analysis of variance (Ryan, Joiner & Ryan, 1982) was used to determine the relationships between various parameters and possession of any particular lymphocyte antigen. For these analyses, FIX were tested for normal distribution using the Shapiro-Wilk test (Ryan et al., 1982). Data were routinely square root transformed for analysis of variance as this resulted in a more normal dist~butio~ than the frequently used log (epg + 15) transformation. Differences in frequency of distribution of OLA between groups were assessed using approp~ate contingency tables. RESULTS Frequency of ULA type

The frequencies of each OLA type in the two flocks examined are shown in Table 2. While the overall pattern of frequencies was similar for ewes and rams and for the two flocks, differences between sexes in the frequency of some antigens were observed (TabIe 2). In particular, SY lb, 6, 13 and 16 were more common in ewes of Flock 1 than Flock 2, and in Flock 1, SY 1b and 14 occurred more frequently in ewes than rams. SY 14 was also more frequent in ewes than rams in Flock 2. There were no differences in the frequency of any OLA type in rams of the two flocks. OLA type in ~eZ~~i~n to sheep FEC

Comparison of the frequency of OLA type between HEC and LEC sheep in Flocks 1 and 2 revealed that the antigen combination SY la + lb was found exclusively in the LEC sheep in both flocks. In addition SY 1a was more common (P < 0.05) in ewes with LEC in Flock 1 and SY 12 and 15 were more common (P 0.01) lower egg count in Phases 1 and 2, SY 6 was associated with elevated egg count regain following ~thel~nti~ treatment. Exa~nation of the Phase 1 data (which comprised nine fortnightly FECs) showed that for those sheep with SY la + lb, the mean FEC at each sampling was lower than the mean

2 7 6

:; la+

18 0 0

3.5

0 0 0 65 6 6 24 12 18

4 6 6

39

:5 21 44

: 2 3 67 6

9 43

(198)

Total

tOLA not detected with antisera panel used.

39

15

lb

3 2 2 3 67 6 17 40 47 22

: 4 5 6 8 9 12 ::

0 12

(17)

(18’) 10 46

Male

Female

la lb

OLA type SY

~-FREQUENCY

Flock 1

TABLE

(%)

OLA

0 8 2

37

3 : 2 41 4 9 53 58 11

7 f5

(97)

Female

of

16 5 8

41

11 0 0 5 62 5 5 35 358

16 22

(37)

Male

Flock 2

101 4

38

48 51 10

51 0 3 47 :

10 17

(134)

Total

SEROTYPES IN ROMNEY

SHEEP

4 :

38

58 5 14 45 51 18

3 :

(278)

Female

17 4 6

39

0 7 0 4 63 6 6 31 309

11 19

(54)

Male

Combined total

4 7 5

39

3 2 1 3 59 5 13 42 47 17

9 33

(332)

Total

Phase 1 1872 1944 1213 1939*** 1858 1917

n 122 59 11 170 66 115

OFFLOCK

~EWE

2nd FEC regain 264** 123 18 231* 114 279***

695*** 381 46 628** 348 734***

9 157**

147** 10 0 109

3rd FEC regain

Phase 2

mean FEC (epg)

SELECTEDANTIGENTYPES

Geometric

WITH

1st FEC regain

LAMBS

Phase 3 270* 126 98 231 118 283**

Mean regain 367** 172 21 322*** 157 388***

*ANOVAR

SY 16+ SY 16gave significantly

12 169

n

greater

liveweight

23.70’ 21.44

Weaning

than SY 16-, P < 0.05.

26.04* 23.20

End Phase 1

Liveweight

31.54* 28.80

End Phase 2

(kg) at:

34.25* 31.62

End Phase 3

ANOVAR on &ursformed data gave significantly greater FEC, *P < 0.10, **P < 0.05, ***PC 0.0 I. tlncludes seven lambs with both SY la + lb in combination and SY 6, also includes those lambs with SY la or SY lb in which SY 6 was not present.

For SY 6 All others ForSY la+ lb All others For SY la + lb and against SY 6t For SY 6

Group selected

TABLE 3-FEC

OLA in Romney sheep

of those without this combination. Those sheep with SY 6 did not have a mean FEC significantly different from those without this antigen at any sampling during Phase 1. ULA type in relation to production parameters (a) height gain. When OLA type frequencies were examined in relation to weight gain during Phase 1 in Flock 1 ewes, SY 9 was significantly (P < 0.05) more common in above-average weight gain animals (23%) than those below average (lo?&). The frequencies of other OLA types in the two groups were not significantly different. SY lb was associated with reduced weight gains in Phase 1 (SY lb+, wt gain 1.38 kg, n = 83; SY lb-, wt gain 2.14 kg, n = 98, P < 0.01) but not in other phases. This was also apparent in those animals with SY (1 a + lb) where weight gain was 0.41 kg (n = 11) compared with those animals not possessing this OLA combination 1.88 kg (n = 170, P <: 0.05). No other antigen type was associated with increased or decreased weight gain. In Flock 2, no association between OLA type and weight gain was found. (b) Livemight. Flock 1 ewes having SY 16 antigen were significantly (P < 0.05) heavier than those without SY 16 throughout the trial (Table 4). No other OLA was associated with such a consistent pattern. In Flock 2, the dist~bution of OLA types in rams and ewes above and below flock mean liveweights was not si~~can~y different. SY 16 was only present in two rams in Flock 2, both were above mean liveweight. OLA type in relation to plasma pepsinogen levels Plasma pepsinogen levels were lower in all phases in those ewes of Flock 1 having SY 2 (P < 0.01-0.001) or SY 3 (P < 0.05-0.01) (Table 5). No other OLA was associated with plasma pepsinogen levels. The small numbers of sheep having SY 2 or SY 3 suggest that these experiments should be repeated with larger numbers of sheep to confirm these associations. C~rnpa~~~n of OLA type ~equency Merino sheep

in Romney and

The Romney sheep examined had lower frequency of SY la, 2,3,4,5,8 and 9 in comparison to Merino sheep, but higher occurrence of SY 6 (Table 6). DISCUSSION The frequency of OLA in the Romney sheep examined differed in the two flocks, particularly with respect to SY lb and SY 6 which were lower in Flock 2 than in Flock 1. In part, this could be a consequence of the selection applied to Flock 2 sheep for production characteristics, SY lb tended to be associated with lower growth rates, and SY 6 associated with higher faecal egg counts. The low overall frequency of SY la in the two Romney flocks would account for the apparent low frequency (5%) of SY la + lb compared with the Merinos (17%) examined by Outteridge et al. (1986).

39

Examination of the relationship between Romney OLA and resistance to nematodes (as determined by low FEC) agreed with the relationship observed previously in Merinos between SY la + lb and low FEC after vaccination and challenge (Ou~e~dge et al., 1986). However, unlike the results in Merinos, the SY la + lb combination in the Romneys was found exclusively in the low FEC sheep of both flocks examined. At each fortnightly sampling during the primary challenge (Phase I), Flock I sheep with these antigens had mean FEC below that of sheep lacking this combination. They were also consistently among the lowest FEC sheep during the subsequent phases. Of particular interest was the observation that in both Romney flocks, SY 6, which was present in higher frequency than in Merinos, showed a positive correlation with FEC. This was particularly marked in Flock 1 ewes after the first anthelmintic treatment (Table 3), when SY 6 was associated with significantly higher FEC. The association of SY 6 with resistance to footrot (Outteridge, unpublished data), and in this study with susceptibili~ to nematode infections, may indicate that selection on the basis of OLA type for one of these traits would tend to select against the other. The notional selection of Flock 1 ewes for SY la -I- lb and against SY 6 yielded a group which, after drenching in March, would have included sufficient numbers of sheep with consistendy low FEC to be potentially useful in a selection programme (Table 3). Considering the low numbers of Romney sheep with SY la, some potential for improvement in resistance appears feasible. The analysis showed that SY 16 was associated with higher ewe liveweight (Table 4). A similar association has been reported in pigs between the swine leucocyte antigen HBe 3 and increased weaning weight (Gautschi, Gaillard, Schwander & Lazary, 1986). In our observations, no OLA was correlated with increased weight gains, but SY lb and SY la + Ib were associated with significantly lower weight gains in one of the flocks examined. The consistency of this association between SY la + lb and SY 1b with low weight gains needs to be examined in other flocks in order to determine if this trait is consistent. Notably, no such association was found in sheep from Flock 2 which had been selected for high growth rate under nematode challenge. The low frequency of some antigens in the Romney flocks examined as compared with those in the Merino sheep (e.g. SY la, 2,3,4,5,9) precluded any me~ing~l analysis of their relationship with FEC or bodyweight. In Merinos, however, SY 2, 3, 5 and 9 have been associated with animals exhibiting susceptibility to nematodes after vaccination (Outteridge, unpublished data). The low frequency of these antigens in the Romney may be a reflection of the generally higher responsiveness of this breed to nematodes. The possibility that the SY la + lb association with low FEC in Merino sheep may have been a fIock

40 TABLE

.%-PLASMA

PEPS~NOGEN

LAMBS IN RELATION

P. G. C.

DOUCH

LEVELS IN FLOCK

1 EWE

TO

and P.

OLA-type

Plasma pepsinogen level (units) n

Phase 1

Phase 2

Phase 3

SY 2+ SY 2-

4 177

0.46 1.08**

0.50 0.92***

0.42 0.87”*

SY 3+ SY 3-

6 175

0.68 1.08*

0.63 0.92**

0.58 0X7**

ANOVAR gave significantly higher pepsinogen level than group with OLA, *P< 0.05, **PC0.01, ***PC0.001. TABLE

~-COMPARISON

OF THE FREQUENCY

R~MNEY

OLA type SY-

AND MERINO

(%I

OF

OLA JN

SHEEP

Romney sheep (n = 332)

Merino sheep (n = 820)

9 33 3 2

26 27 8 8 5 25 32 14 29 n.d. n.d. n.d. n.d. n.d. 17

la lb 2 4 6 8

9 12 13 14 1.5 16 la+lb

3 59 1: 42 17 47 39 4 5

n.d., Not determined. effect resulting from the selection and mating of particular sires was raised previously (Outteridge et al., 1986). However, exclusive association of SY la I- lb with the Romney sheep in both Flock 1 and Flock 2 supports the view that it is not a foundation effect, although it cannot be ruled out. It should be pointed out that these putative MHC effects on the responsiveness of sheep to parasite antigens would most likely be evident after immunological priming. The results from Flock 1, Phases 2 and 3, indicate that most sheep acquire immunity with time but that significantly greater resistance to nematodes than average as indicated by FECs was acquired by animals having the SY 1a + 1b combination. It is also noteworthy that even during Phase 1, the sheep with SY la + lb appeared to have sig~ficandy increased resistance to nematodes compared with other types, at a time during which the primary antigen recogmtion was being established. Earlier work with T. colubriformB infection of Merino sheep (Outteridge et al., 1985) was carried out using initial immunizing steps at 8 and 12 weeks foundation

M.

OUTTERIDCE

with irradiated larvae, then an~el~ntic treatment, followed by challenge with normal larvae. This protocol may have had elements in common with the present management protocol for the Romney sheep, with natural exposure to larvae, treatments with anthehnintic, followed by exposure to larvae again. Therefore the common finding of the SY la + 1b association with low FEC points to the same mechanism of immu~ty and the same influence of the OLA system on immune responsiveness to parasites in the two breeds of sheep. At present, definitive evidence involving MHCrestricted immune mechanisms for parasite resistance in sheep is lacking but evidence from mice (Wassom, David & Gleich, 1979) suggest that the H-2 complex, IA region haptotype of mouse strains influence their primary resistance to Trichinella spiralis. However other genes, as yet incompletely identified (the ‘background genes’), are also impo~ant in resistance to T. spiralis in these inbred strains of mice. It has also been suggested that in an immune response, the T4 and T8 lymphocyte antigens serve as associative recognition elements for class II and class I MHC antigens, respectively (Gorrell, Mackay, Maddox, Rickard & Brandon, 1986) and that these may be the important elementsin diseaseassociations. However, it is generally accepted that initial antigen recognition involves binding of antigen epitopes directly to class I or class II MHC glycoproteins and that this variation in binding may parallel haplotype differences in responsiveness of different mouse or rat strains to defined antigens (Paul, 1984; Butcher & Howard, 1985). Therefore, the MHC gene products are strong candidates for initial recognition elements of foreign antigen in the sheep too, with alleles of these genes being likely to be invoived in the variation in j~une responsibleness. On the other hand, genes linked to the MHC but not part of the complex, have been implicated in numerous non-immune functions (Edidin, 1983) and it is possible that the associations we have found between OLA type and resistance to nematodes reflect the function of the linked genes rather than immune response genes. In the present experiments, the significantly reduced pepsinogen levels in those Flock 1 ewes with SY 2 or SY 3 were associated with a tendency towards lower Phase 1 mean FEC (SY 2+/-, 1133/1913 epg; SY 3 +I; 1.581/1906 epg). This is in agreement with the elevated plasma pepsinogen levels usually observed in heavily parasitized ruminants. However, low FEC was not generally associated with low pepsinogen levels, for example, SY 6 negative sheep and those with SY la i- lb OLA types had pepsinogen levels similar to the flock mean level. Thus the association of SY 2 and SY 3 with low pepsinogen levels is int~guing because it may reflect a closely linked gene on the same chromosome in the sheep which controls either the amount of pepsinogen synthesized or which is involved in the limitation of mucosal damage caused by parasites. Such findings

OLA in Rclmney sheep will need to be examined in experiments with larger numbers of animals having these OLA types. This study indicates that, although present in low frequency, the OLA SY la + lb may be useful as a predictive marker for resistance of Romney sheep to nematodes. In addition, the associations of SY 6 with high FEC and SY 16 with high liveweight warrant further evaluation as practical markers. Acknowledgements-The authors thank Mrs Karleen Glen, Mrs Pauline Morum (Wallaceville ARC), Miss Judy Tompson and Miss Karen Trott (McMaster Lab.) for their technical assistance. The authors also wish to thank Dr R. V. Brunsdon, Mr S. Bisset and Mr A. Vlassoff (Wallaceville ARC) for parasitological and production data and for access to the Romney flocks. PGCD also thanks the CSIRO for the opportunity to visit the McMaster Laboratory.

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41

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