Gamete-level immunogenetic incompatibility in humans-towards deeper understanding of fertilization and infertility?

Abstract

Human leukocyte antigen (HLA) immune genes play an important role in partner selection, but it has remained unclear if nonrandom pairing with respect to parental HLA genes could occur at the level of the gametes. We tested this possibility by investigating whether the sperm fertilization competence in humans is dependent on HLA genotype combination of the partners. We conducted a full-factorial experiment, in which the sperm physiological preparation for fertilization among multiple males was studied in the presence of follicular fluid (oocyte surrounding bioactive liquid) of several females. All the studied sperm pre-fertilization physiological parameters (motility, hyperactivation, acrosome reaction, and viability) were strongly dependent on male-female combination. In other words, follicular fluids (women) that induce strong sperm physiological response in some males often induce much weaker response in the other(s). Sperm physiological responses were stronger in HLA-dissimilar male-female pairs than in HLA-similar combinations, but none of the measured sperm traits were associated with genome-wide similarity. Together, these findings shed new light on the evolutionary and immunological mechanisms of fertilization. Furthermore, our results raise an intriguing possibility that against currently prevailing WHO's definition, infertility may not represent exclusively a pathological condition, but may also result from immunogenetic incompatibility of the gametes.

Fig. 1. Sperm motility in different male-female combinations.

The effect of male–female interaction (combination) on sperm swimming velocity (±s.e.m.) (a) and the proportion of hyperactivated sperm cells (±s.e.m.) (b) 300 min after the initiation of the follicular fluid treatment. Bar colors representfemale identity (n = 10), within each male (1–8).

Fig. 2. Relative contribution of males, females, and male–female interaction on sperm motility.

Proportion of variance explained by males, females, and male–female interaction (combination) in sperm swimming velocity (VCL) (a) and hyperactivation (b) 30–300 min after the initiation of the follicular fluid treatment.

Fig. 3. Sperm acrosome reaction and viability in different male-female combinations.

The effect of male–female interaction (combination) on thesperm acrosome reaction (±s.e.m.) (a) and the proportion of dead sperm cells (±s.e.m.) (b). Bar colors represent female identity (n = 10), within each male (1–8).

Fig. 4. The association between male–female HLA similarity (number of shared alleles) and sperm swimming velocity (VCL).

The slope in the figure describes predicted (i.e., modeled) average effect of HLA similarity on VCL in eight males. To control between male differences in intrinsic sperm quality, the slope was modeled in individual male level, when the average slope of eight males was clearly negative (intercept: 177.6; slope: −1.10, P = 0.003). The slope of the association did not vary across males (P = 0.28).