Homosexuality: is it a choice? Immune hypothesis and fraternal birth order.
Life Style

Author: Anna Guardia Federica Cavaglia
Date: 11/02/2013



Homosexuality is romantic or sexual attraction or behavior between members of the same sex or gender.
Why does homosexuality exist? What does determine it? Is it a choise or is it a predisposition?
There are many studies that say that: a mother develops an immune reaction against a substance important in male fetal development during pregnancy, and that this immune effect becomes increasingly likely with each male gestation. This immune effect is hypothesized to cause an alteration in later born males’ prenatal brain development. The target of the immune response may be molecules (Y-linked proteins) on the surface of male fetal brain cells, including in sites of the anterior hypothalamus and nucleus of the preoptic area, which have been linked to sexual orientation. Antibodies might bind to these molecules and thus alter their role in typical sexual differentiation, leading some later born males to be attracted to men as opposed to women. There is a evidence that mothers of boys develop an immune response to one Y-linked protein (H-Y antigen; SMCY) important in male fetal development, and that this immune effect becomes increasingly likely with each additional boy to which a mother gives birth.

Wikipedia: Homosexuality .

Molecular biology of testis determination

During gestation, the cells of the primordial gonad that lie along the urogenital ridge are in a bipotential state, meaning they possess the ability to become either male cells (Sertoli and Leydig cells) or female cells (follicle cells and Theca cells). SRY initiates testis differentiation by activating male-specific transcription factors that allow these bipotential cells to differentiate and proliferate. SRY accomplishes this by upregulating SOX9 , a transcription factor with a DNA-binding site very similar to SRY's. SOX9 in turn upregulates fibroblast growth factor 9 (Fgf9), which is necessary for proper Sertoli cell differentiation. Fgf9 then feeds back and upregulates SOX9. SOX9 can also upregulate itself by binding to its own enhancer region (positive feedback loop). Once proper SOX9 levels are reached, the bipotential cells of the gonad begin to differentiate into Sertoli cells. Additionally, cells expressing SRY will continue to proliferate to form the primordial testis. While this constitutes the basic series of events, this brief review should be taken with caution since there are many more factors that influence sex differentiation.

Wikipedia: Molecular biology of testis determination .

Maternal immune response

According to the maternal immune hypothesis (MIH) of male sexual orientation development, FBO results because some mothers develop an immune response to a substance important in male fetal development. This immune effect would increase in likelihood with each male fetus gestated by the mother; thus, an affected son would exhibit a heightened number of older brothers (hence a ‘‘FBO effect’’). Presumably, the process would begin when cells from a male fetus enter a mother’s circulation during pregnancy or childbirth. Given these cells originate from males, they would include on their surfaces (or inside them) male-specific substances (Y-linked proteins) that are antigenic to the mother; as such, her immune system would recognize these substances as ‘‘foreign’’ given that she herself is female. Despite immunomodulation occurring in pregnancy, the mother would develop antibodies against these substances, and antibodies would cross the placental barrier and enter the fetal compartment. These anti-male antibodies would also then cross the blood/brain barrier (BBB) of the immature fetal brain, and ultimately affect brain development. Specifically, these antibodies would alter sex-dimorphic brain structures relevant to sexual orientation, and the affected son would ultimately become attracted to men as opposed to women. The degree to which this immune effect alters brain development would depend on the number of antibodies that reach the relevant brain structure and the binding strength of these antibodies to male-specific substances. As both the number and binding affinity of antibodies generated significantly increase during a memory immune response—in subsequent male pregnancies when male-specific substances are encountered the second (or third, etc.) time by the maternal immune system—the likelihood of the immune effect on sexual orientation becomes higher in subsequent male pregnancies, and hence the FBO effect.

A number of conditions must exist if the MIH is a viable explanation of FBO.

First, there must be evidence that fetal material enters the maternal circulation. A review of the relevant research indicates that this condition is well-established. High levels of different fetal cells enter the maternal circulation during abnormal pregnancies; however, there is also evidence that a variety of cells regularly enter maternal circulation throughout normal pregnancies.

A second condition for MIH to be a viable explanation of FBO is that a male-specific substance should cause immune responses in females. This condition is also clearly established. A class of molecules derived from male tissues known collectively as H-Y (histocompatibility-Y) antigens cause immune reactions in females exposed to them.
The most commonly studied form of H-Y antigen was originally detected via transplants, and is designated by the gene SMCY , or JARID1D (also known as HY). A series of peptides derived from the protein encoded by SMCY are typically used in H-Y immunological research.

Third condition for the MIH to underlie FBO and its effect on sexual orientation is that the relevant Y-linked substance should play some role in the sexual differentiation of the brain, including, presumably, lower-brain structures hypothesized to be important in sexual orientation development.
These proteins are:
protein coded by SMCY is expressed in the brain, and thus may play a key role in sexual differentiation of it. It seems plausible, then, that this gene could contribute to the sexual differentiation of those reproductively relevant brain structures such as hypothalamic sites. A complication in the SMCY protein underlying the MIH and FBO is that, along with it being expressed in male brain cells, it is also well represented in gonad cells, including sperm, and in other parts of the male body. The question, then, is whether a mother’s immune system could target H-Y and affect brain mechanisms underlying sexual orientation but not affect the development of the body, including the genitals and sperm production. This question is important because there are likely only minor physical differences between gay and heterosexual men, and there is no evidence that gay men have lower fertility relative to heterosexual men. In fact a maternal immune response against H-Y may also not affect sperm in a fetus, as they are immature, underdeveloped and only reach maturity during adolescence. An additional complication is that the SMCY protein is expressed within and not on the surface of cells. SMCY is broken down into peptides and these peptides are expressed on the surface of cells by the Major Histocompatibility Complex (MHC) class I protein for allowing the body to recognize them as ‘‘self’’ through MHC processes.
Protocadherin 11-linked (PCDH11Y ) : codes for a protein important in cell adhesion and is predominantly expressed on the surface of brain cells. It is involved with synapse formation and neural pathway development. It is predominantly expressed in the brain, it may play an important role in gender differences in behavior and cognitive processing unique to humans. An immune response against the PCDH11Y protein may alter one or more of these sex-linked traits/behaviors and ultimately lead to atypical sexual attraction patterns in men.
Neuroligin 4 Y-linked (NLGN4Y ): codes for a protein involved in cell adhesion and is well-expressed in the brain, although it is also expressed in other regions, including the genitals and prostate. This protein is primarily ex- pressed at the postsynaptic side of the synapse and is thought to play an important role in synaptic functioning. It is also expressed on the surface of cells and thus makes it accessible to antibodies. This gene may also ultimately code for different protein isoforms at different tissue sites, only one of which may be relevant to sexual orientation development (and thus the target of a maternal immune response underlying FBO).
TBL1Y : is well-expressed in the brain, although it is expressed within cells and not on their surface. A maternal immune effect against this protein might also affect the body and not just brain structures relevant to sexual orientation development.

A fourth condition for the MIH to be a plausible explanation of FBO is that there should be evidence that a maternal immune response to Y-linked proteins affects fetal development, including, potentially, sexual differentiation of the brain.

A fifth condition for the MIH to be a plausible explanation of FBO is that the maternal immune response to Y-linked proteins should show an incremental response to previous male fetuses similar to the incremental pattern that the FBO effect has on male sexual orientation for each additional older brother. This has been established for H-Y: Piper and colleagues showed that 37% of women with a male pregnancy had a detectable immune reaction to H-Y peptides; and this amount increased to 50% with two or more male pregnancies.

The male-specific histocompatibility antigen , E. Simpson, D. Scott, P. Chandler, 1997.

H-Y Antigen and Homosexuality in Men , R. Blanchard and P. Klassen, 1997.

Sexual orientation, fraternal birth order, and the maternal immune hypothesis. , A. F. Bogaert, M. Skorska, 2011.


To explain homosexuality many hypotheses have been advanced: from nativism to evolutive role, from genetic modifications to reproductive and adaptative strategies. However the proposed aetiological theories were not able to get the scientific reliability to exclude all other theories. These are the positions taken on the subject by the major global institutions.

The Royal College of Psychiatrists stated in 2007:
Despite almost a century of psychoanalytic and psychological speculation, there is no substantive evidence to support the suggestion that the nature of parenting or early childhood experiences play any role in the formation of a person's fundamental heterosexual or homosexual orientation. It would appear that sexual orientation is biological in nature, determined by a complex interplay of genetic factors and the early uterine environment. Sexual orientation is therefore not a choice.

The American Academy of Pediatrics stated in Pediatrics in 2004:
Sexual orientation probably is not determined by any one factor but by a combination of genetic, hormonal, and environmental influences. In recent decades, biologically based theories have been favored by experts. Although there continues to be controversy and uncertainty as to the genesis of the variety of human sexual orientations.

The American Psychological Association states:
"there are probably many reasons for a person's sexual orientation and the reasons may be different for different people", and says most people's sexual orientation is determined at an early age. Research into how sexual orientation in males may be determined by genetic or other prenatal factors plays a role in political and social debates about homosexuality, and also raises fears about genetic profiling and prenatal testing.

Professor Michael King states:
"The conclusion reached by scientists who have investigated the origins and stability of sexual orientation is that it is a human characteristic that is formed early in life, and is resistant to change. Scientific evidence on the origins of homosexuality is considered relevant to theological and social debate because it undermines suggestions that sexual orientation is a choice."

Wikipedia: Homosexuality .

Cavaglià Federica
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