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The Journal of Theoretical Fimpology. Volume 1, Issue 2: e-20130512-1-2-4. May 18, 2013 (www.fimpology.com)

A Noninherited-Paternal-Antigen-Centric Model for the Birth Order and Sibship Size Effect in Transplantation Immunology

Shu-dong Yin

ORCID 0009-0005-8661-6889

Cory H. E. R. & C. Inc., Burnaby, British Columbia, Canada
Email: [email protected]

Abstract

The survival of grafts at the individual macroorganism level involves in a complex tolerogenic mechanism. In humans, the relationship between the fetus, postnatal offspring, mother and biological father has been revealed to be associated with tolerogenic mechanisms in clinical transplantation, among which, the model of maternal-to-fetal cell transmission mediated tolerance to noninherited maternal antigens (NIMAs) was once highlighted. However, the NIMAs-centric theory along cannot explain the birth order effect and the NIMA paradox. Recently, six models of pregnancy-associated eukaryotic cell transmissions were summarized: fetus-to-maternal cell transmission (FMCT), maternal-to-fetal cell transmission (MFCT), gestation-associated fetus-to-fetus cell transmission (FFCT), breastmilk and breastfeeding-mediated maternal-to-infant cell transmission (MICT), breastmilk and breastfeeding-mediated fetus-to-infant allogenic or inter-sibling cell transmission (FICT), the fetus-breastmilk-breastfeeding-infant-cells cycle (FBBIC Cycle). Based on these advances, I propose a novel theoretical model called noninherited-paternal-antigen-centric model (NIPA-CM) for understanding the birth order and sibship size effect in transplantation immunology. NIPA-CM illustrates that FFCT and FICT may play a role in transferring noninherited paternal antigens (NIPAs) to introduce sibling tolerance to them, and moreover, the variation of intersibling tolerance to NIPAs may depend on both birth order and sibship size.

Key Words: noninherited maternal antigens (NIMAs); noninherited paternal HLA antigens (NIPAs); birth order; sibship size; cell migration

Introduction

Six decades ago, the concept of "acquired immunologic tolerance" was first proposed by Billingham, Brent and Medawar [1-3]. In a retrospective study, Burlingham and colleagues showed that the survival rates of kidneys from siblings expressing maternal HLA antigens not inherited by the recipient were better than those of kidneys from siblings expressing paternal HLA antigens not inherited by the recipient [4]. Moreover, later studies on clinical cellular transplantation showed that blood and marrow stem cell transplants from mother to child had better survival than that from paternal grafts [5,6]. Despite many unknowns and debates, this survival difference was partly accounted for by the prenatal noninherited maternal antigens (NIMA)-induced tolerance theory [3,4,7-16]. However, the NIMA-centric theory cannot account for the birth order effect and the NIMA paradox [4,14,17] in clinical transplantation.
During the past two decades, accumulating evidences from studies on humans and non-human mammals have indicated that there are different eukaryotic cell transmissions among mothers, fetuses and infants during gestation and lactation. Recently, six models of eukaryotic cell transmission among mothers, fetuses and infants during gestation and lactation have been summarized: (i) FMCT, (ii) MFCT, (iii) FFCT, (iv) MICT, (v) FICT, and (vi) FBBIC Cycle [29]. Based on the this progress, I further propose a novel theoretical model called noninherited-paternal-antigen (NIPA)-centric model (NIPA-CM) for understanding the birth order and sibship size effect in transplantation immunology.

Hypothesis and Discussion

I. NIMA-centric model

The NIMA-induced tolerance theory was illustrated by Burlingham and colleagues in their NIMA-centric model (a hypothesized family with two parents and three offspring) [4], in which, it was assumed that the mother had alleles C and D of the gene for an HLA antigen; and the father had alleles E and F of the same gene. According to Mendel's law of inheritance, each offspring of them got one allele (C or D) from the mother and the other (E or F) from the father, and therefore, the alleles for encoding the HLA antigen in each offspring were one of the following four possibilities: CE, CF, DE and DF. If an offspring got allele D from his or her mother, then C was called a noninherited maternal allele, and the antigen encoded by C was described as a noninherited maternal antigen. Similarly, if the offspring obtained E from his or her father, then F was called the noninherited paternal allele, and the antigen encoded by F was noninherited paternal antigen [4] (see Figure 1).
In Burlingham's model, each offspring during his or her fetal life was hypothesized not to have been exposed to the noninherited paternal HLA antigens (NIPAs) encoded by the noninherited paternal alleles [4], which restricted its accounting for the clinical phenomenon described by Opelz in 1990 that the survival of renal allografts donated by mothers and fathers had no clinical difference [4], or later called "the NIMA Paradox" by Burlingham and Benichou [17], and the birth order effect on the variation of inter-sibling tolerance found by Bucher and colleagues in 2007 [14].

II. The birth order and sibship size effect

The sibship size and the birth order in epidemiological studies have been showed to associate with allergic disorders, in which, asthma and atopy were found to be less common in younger siblings than in elder siblings [18-22].
In recent years, siblings have increasingly gained attention as an important donors for cellular and organ transplantation [12,23-26]. Bucher and colleagues first described the phenomenon of the birth order effect on the variation of inter-sibling immune-tolerance in a retrospective study on allogenic hematopoietic stem cell transplantation (HSCT), in which, cellular grafts from younger siblings significantly decreased the risk of graftversus-host disease (GVHD) in recipients who were born as the first children of families [14,27]. However, Gratwohl and colleagues later found no birth order effect in their analysis of HLA-identical living sibling donor kidney transplantations [28].

III. The association of prenatal and postnatal eukaryotic cell transmission with NIMAs- tolerogenic and NIPAs- tolerogenic mechanisms

In normal pregnancies, fetus can come into contact with NIMAs via maternal fetal molecular chimerism and maternal fetal cellular chimerism (the latter is also called the maternal cell transmission to the fetus, MFCT), which is believed to produce immune tolerance to NIMAs in the offspring. In contrast, the father does not have such advantages in allowing the fetus to be exposed to NIPAs to produce immune tolerance to NIPAs except delivering DNA molecular information to the offspring via Mendel’s Hereditary Law.
So far, two tolerogenic mechanisms at the cellular level have been discussed: one is the deletion of alloantigen-reactive T cells [13,30,31]; and the other is the development of tolerogenic fetal T regulatory cells (Tregs) during gestation [3,31,32]. A few studies have revealed that there were no differences in the frequencies of cytotoxic T cell precursors (CTLp) and IL-2-producing helper T cell precursors (HTLp) against the noninherited maternal and the paternal HLA antigens [10], or cell-mediated lympholysis response [9].
In regards to exposure to NIMAs, the offspring can come into contact with NIMAs via both prenatal and postnatal mechanisms. For example, in HLA-A2 negative babies born to HLA-A2+ mothers, soluble HLA-A2 (sHLA-A2) is a type of noninherited maternal antigen (NIMAs), and such NIMAs can be exposed not only by HLA-A2 negative fetus during pregnancy, which was confirmed by the detection of NIMA HLA-A2 in cord blood, but also exposed postnatally via breastfeeding through the detection of NIMA HLA-A2 in human milk from HLA-A2+ mothers [37]. It is clear that exposure to noninherited maternal HLA antigens may also occur during lactation via both molecule exchange at the molecular level and maternal-infant microchimerism at the cellular level, while the infant is breastfeeding with milk from his or her own biological mother [37,38].
Recently, van Rood and colleagues proposed another possible mechanism involving the microchimerism of maternal memory T cells anti-inherited paternal antigens (IPAs) of the fetus [27]. In fact, the possibility of exposure to NIPAs during gestation via prenatal FFCT has been suggested in a few of studies [14,33,34-36]. Moreover, paternal alloantigens-tolerogenic fetal and maternal T regulatory cells (PATFM Tregs) were hypothesized to play a role in postnatal antipaternal immune reaction to paternal antigens [29].
Theoretically, fetus and/or infant actually can also obtain tolerance to NIPAs through the following four mechanisms: (1) residual fetal cells from previous pregnancies in the The Journal of Theoretical Fimpology. Volume 1, Issue 2: e-20130512-1-2-4. May 18, 2013 www.fimpology.com Copyright © 2013-2023 by Cory H. E. R. & C. Inc. All Rights Reserved. 5 maternal body can migrate into the fetal body of next pregnancy via FFCT, regardless of whether previous pregnancies were premature or matured, and whether they were aborted or completed normally; (2) residual fetal cells from previous pregnancies enter the body of the suckling infant via breastmilk and breastfeeding-mediated FICT; (3) FBBIC Cycle, in which fetal cells of the current pregnancy may be prenatally exposed to NIPAs and regained postnatally by the infant him- or her-self via breastfeeding; and (4) tolerogenic maternal regulatory T cells to NIPA via prenatal MFCT and postnatal MICT.

IV. The birth order and sibship size-related NIPA-centric model

Based on Burlingham's NIMA-centric model [4], I propose a model called "the noninherited paternal antigens-centric model" (NIPA-CM), in which, the mother in the hypothesized family is assumed to have had no silent or identified abortions before delivering her first living offspring. Both NIMAs and NIPAs are hypothesized to be exposed to offspring during gestation and lactation via MFCT, FFCT, MICT, FICT, and FBBIC Cycle.
Surprisingly, the coexistence of the birth order effect and the sibship size effect on the variation of inter-sibling tolerance emerges, which may theoretically account for "the NIMA Paradox". Interestingly, in this birth order and sibship size-related NIPA model, the exposure to NIMAs via prenatal MFCT and FFCT and postnatal MICT, FICT and FBBIC Cycle dose not show any birth order and/or sibship size effect because each offspring has opportunities to contact NIMAs via both prenatal and postnatal multiple routes (see Figure 2).
Generally speaking, in single pregnancy mammals, prenatal FFCT and MFCT and postnatal FICT, MICT and FBBIC Cycle may offer later-born siblings the chance to be exposed to NIPAs carried by their elder siblings or previously aborted embryos/fetuses, and therefore, to induce tolerance to NIPA. In contrast, the elder siblings have no chance to contact NIPAs carried by their younger siblings and therefore no yielded tolerance to NIPAs carried by younger siblings.
Theoretically, the survival rate of grafts from older siblings in younger sibling recipients is usually higher than that of grafts from younger siblings in elder sibling recipients, meaning less graft rejection in younger sibling recipients, and less graftversus-host disease (GVHD) in elder sibling recipients.
In the NIPAs-centric model (see Figure 2), each younger siblings may have both prenatal and postnatal opportunities to expose to NIPAs carried by the first child in a family, but the eldest sibling has no chance to expose to NIPAs carried by his or her younger siblings, which may account for Bucher and colleagues'finding [14].
Moreover, the inter-sibling tolerance between the first child and their younger siblings in a family is influenced by birth order, while the inter-sibling tolerance among those young siblings is mainly affected by the random birth orders that are dependent on sibship size. For example, in the six-child family model (see Figure 1), there are 4096 total probabilities for the random birth orders of six siblings for the alleles of a gene. The chance for the eldest offspring to be exposed to NIPA E or F for is zero, while it is 50% (2048/4096) for the second child, 75% (3072/4096) for the third offspring, 87.5% (3584/4096) for the fourth offspring, 93.75% (3840/4096) for the fifth one, and 96.88% (3968/4096) for the youngest sibling, the sixth offspring.
However, it worth to point out three special orders: (i) all offspring in a family have the same alleles of a gene for inherited paternal and maternal antigens. In other words, there are no NIMAs and NIPAs among siblings, but NIMAs between maternal body and offspring. Therefore, theoretically, prenatal FFCT and postnatal FICT and FBBIC Cycle cannot offer a chance to each offspring to contact NIPAs, in contrast, each offspring may contact NIMAs via prenatal MFCT and/or FFCT, and/or postnatal MICT, FICT and FBBIC Cycle (see Figure 3), (ii) all offspring in a family have the same alleles for inherited paternal antigens and different alleles for inherited maternal antigens (see Figure 4), and (iii) all offspring have the same alleles for inherited maternal antigens and different alleles for inherited paternal antigens (see Figure 5).
Clearly, in the NIPAs-centric model, the exposure to NIPAs may occur only when offspring of the different birth orders bear different alleles for inherited paternal antigens. In contrast, the exposure to NIMAs can occur via prenatal MFCT and postnatal MICT and FBBIC Cycle, even if all offspring share the same maternal allele (C or D).
When the hypothesized family has two-offspring, the random birth order of two siblings for the alleles of a gene has total 16 probabilities, and the chance for the eldest brother or sister to contact NIPA E or F via FFCT and FICT, or even FBBIC Cycle is zero; in contrast, that for the second offspring to be exposed to either NIPA E or F is 50% (8/16). Moreover, the chance for both the firstborn sibling and the second offspring to match both NIMA and NIPA is 25% (4/16); and therefore, for the second-born sibling the chance of tolerance to NIPA E or F is higher than that for the firstborn sibling.
In the family with three siblings, the random birth order of three siblings for the alleles of a gene has a total of 64 probabilities. The chance for the firstborn offspring to contact NIPA E or F via FFCT, FICT and FBBIC Cycle is zero; in contrast, the chance for the second offspring to be exposed to either NIPA E or F is 50% (32/64); and that for the third-born offspring, the youngest sibling, to contact NIPA E or F is as high as 75% (48/64).
When sibship size increases to four, the random birth order of four siblings for the alleles of a gene has a total of 256 probabilities. The chance for the firstborn brother or sister to contact NIPA E or F is still zero; but the chance for the second offspring is 50% (128/256), for the third is 75% (192/256), and for the fourth offspring, the youngest sibling is 87.5% (224/256).
In a five-sibling family, the random birth order of five siblings for the alleles of a gene has a total of 1024 probabilities. The chance to be exposed to NIPA E or F is zero for the first offspring; 50% (512/1024) for the second one; 75% (768/1024) for the third offspring; 87.5% (896/1024) for the fourth offspring, and 93.75% (960/1024) for the fifth one, the youngest sibling.
In the six-sibling microchimeric model, the random birth order of six siblings for the alleles of a gene has a total of 4096 probabilities. The chance to be exposed to NIPA E or F for the eldest offspring is zero, 50% (2048/4096) for the second one, 75% (3072/4096) for the third offspring, 87.5% (3584/4096) for the fourth offspring, 93.75% (3840/4096) for the fifth one, and 96.88% (3968/4096) for the youngest sibling, the sixth offspring.
The possible reason for the Gratwohl and colleagues’ failure to show the birth order effect [28] may be due to their simply division of 6062 cases into two groups: (1) donor younger than recipient, and (2) donor older than recipient [28]. In fact, according to the NIPAs-centric model, the chance to being exposed to NIPA E or F for a later-born sibling increases as the sibling size increases.
Theoretically, the first living offspring in the hypothesized family should be the result of the first pregnancy that the mother experienced, and under this strict definition, the chance of being exposed to NIPA E or F for the first-born offspring is always zero. However, in fact, many women may have experienced previously silent abortions or unsuccessful pregnancies before having delivered their first living baby, which should be given special attention in future laboratory and epidemiological studies.

V. Murine models in the experimental animal study on tolerogenic mechanism

It is worth to point out that theoretically, in multiple pregnancy animals, such as mice, rats, and pigs, the chance of exposure to NIPA should be equal in every one of littermates [29]. Therefore, multiple pregnancy animals may not be a suitable experimental model for studying the birth order and sibship size effect in transplantation immunology.
In the experimental animal study, the murine model used by Andrassy and colleagues was the product of H-2(b/b) males mating with H-2(b/d) females [13], which, however, is suitable for studying the NIMAs mechanism but not for others because they are multiple pregnancy mammals and theoretically, there should be a fetus-to-fetus cell transmission or exchange during their normal gestation [29]. Therefore, the murine offspring of H-2(b/d) males mating with H-2(b/b) females may be suitable for studying NIPAstolerogenic mechanism, FFCT, and FICT.

Conclusion

The survival of grafts is a synthetic manifestation at the individual macroorganism level, meaning the mechanisms involved in tolerance are complicated; and in fact, there are still some critical questions to be answered. The NIMAs-centric model alone cannot account for the birth order effect and the NIMAs paradox in transplantation immunology. The novel theoretical model proposed in the manuscript shows that the variation of intersibling tolerance to NIPAs via FFCT and FICT is associated with birth order and sibship size, and that the first-born child has no chance to contact NIPAs carried by his/her younger siblings, and therefore, no tolerance to those NIPAs. In contrast, prenatal FFCT and MFCT and postnatal FICT, MICT and FBBIC Cycle may offer later-born siblings the chance to be exposed to NIPAs carried by their elder siblings or previously aborted embryos/fetuses, and therefore, to induce tolerance to those NIPAs.

Abbreviations

FMCT: gestation-associated fetus-to-maternal cell transmission;
MFCT: gestation-associated maternal-to-fetal cell transmission;
FFCT: gestation-associated fetus-to-fetus cell transmission;
MICT: breastmilk and breastfeeding-mediated maternal-to-infant cell transmission;
FICT: breastmilk and breastfeeding-mediated transmission of sibling and allogenic fetal cells into infantile body;
FBBIC Cycle: fetus-to-infant his/her own fetal cell external transmission via breastfeeding;
FMMC: fetal-maternal microchimerism;
MFMC: maternal-to-fetal microchimerism;
FFMC: fetofetal microchimerism;
MIMC: maternal-infantile microchimerism;
FIMC: fetoinfantile microchimerism;
NIPAs: noninherited paternal antigens;
NIMAs: noninherited maternal antigens.

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