3: Allorecognition, Alloreactivity, Sexuality

Teresa Binstock binstoct at essex.UCHSC.edu
Fri Apr 25 15:47:15 EST 1997


Continuation of:
      ti: Allorecognition and alloreactivity: a primary substrate
    	  of human sexuality. 			  (part 3 of 3)
      au: Teresa C. Binstock   			       (c) 1997
      so: bionet.immunology    			  April 25 1997

3: Allorecognition, Alloreactivity, Sexuality

                       SOME IMMUNO TIDBITS
                TOWARDS UNDERSTANDING VARIATIONS
               IN SEXUAL- AND GENDER-ORIENTATIONS

ENDOCYTOSIS: Many antigen-presenting cells (eg, in the nasal and
oral mucosa) will respond to small molecules and will process
many of these into peptides that fit into binding cites of MHC-II
or MHC-I molecules. The antigenic molecule will enter a surface
cell via an endocytic process and will be modified into an MHC-
presented peptide accessible to T- and/or B-cells.

MACROPINOCYTOSIS (MCP): MCP refers to a process whereby larger
fragments can induce an immune response. Dendritic cells are a
cell-type that can intake cells and/or cell fragments via MCP.

CROSS-PRIMINGS: Desquamated skin is a natural occurrence within
each of us -- eg, within our oral cavities. An ongoing rate of
responding to our own desquamated skin (and its 2 of HX, in XX
females; its 1 of HX and 1 of HY in males) is a normal part of
our existence and is so perceived by our epithelial immune cells.
However, in some individuals, the rate of desquamation may be
increased and/or immunological responses to the desquamated cells
may be made stronger. When this occurs, a condition known as
"cross-priming" can occur. Cross-priming refers to an
immunological antigen being presented within the wrong MHC
pathway. In other words, MHC-I molecules tend to present proteins
endogenous to the individual, and MHC-II molecules tend to present
proteins from sources exogenous to the individual. However, a
number of process are known whereby a self-molecule may be
perceived via a MHC-II presentation; or similarly, an exogenous
molecule may be perceived via a MHC-I presentation. These cross-
primings (in ways related to HY or lack thereof), in some
individuals, may be a primary mechanism by which an alteration in
sexual- and/or gender orientation occurs, although other T-cell
and/or B-cell alternations are possible too.

INFECTIONS & CROSS-PRIMINGS: Infections oftentimes lead to
enhanced cellular death within infected tissues. An excess of
cross-priming events (eg, an XY-male's own HY-antigens becoming
seen in too many cells of his own MHC-II pathway) might lead to
that male's acquiring an alternative response-pattern to HY-
encoded cells and cell fragments from other persons. 
1.   If this happened early in life (eg, in utero), then his
primary gamma delta T cells (Vg9/Vd2) that are aware of HY and
have SRY expressed (McVAY & Carding, 1996), might be changed on a
very deep level in regard to sense of self as an XY/HY organism;
and these cells are headed for mucosal epithelia later in life,
where via allorecognition and alloreacitivity mechanisms specific
subsets of the person's epithelial immune cells would
also subsume the person's perceptions of other humans. 
2.   Nearly concurrently, CD5+ B-cells are coming on line; these
cells too have a strong sense of self (eg, Kasaian & Casali
1993).
3.   An additional timing is neonatal, during which intestinal
CD5+ B-cells are acquiring a sense of self -- even in regard to
intestinal flora -- and, we might presume, to a low and natural
level of desquamated cells and cell fragments from the intestinal
tract (Kroese et al 1996). 
4.   Certain data from intestinal studies suggest ways that a
bacterial infection could alter T-cell function in the liver and
in the intestines. Within the liver, such an infection induces
"the appearance of T cells bearing self-reactive T cell receptors
..." (Abo T et al 1991). Furthermore, since some bacterial
infections can be present in the intestines, and since intestinal
T-cells and many of their subsets are part of the "common mucosal
immune system" (eg, Brandtzaeg ANYAS 779.1-27 1996), intestinally
induced T-cell variations could have effects upon immunity within
upper mucosal epithelia. If additional cells die (eg, from the
person's own GI-tract), then via macropinocytosis and other
cross-priming processes, he or she could acquire T-cell
atypicality in response to HX and/or to HY antigens, not only in
the liver or intestines, but possibly in upper mucosal epithelia
as well. If this occurred early in life (ie, neonatal), then
intestinal CD5+ B-cells and their prominent self-encodings might
also be affected.
5.   The presence of bacteria may also activate extrathymic T
cells in the liver and, reciprocally, inactivate intrathymic T
cells temporarily (Abo T et al 1992). As a result, thymic
encodings during this time will occur minimally, thereby
providing further alterations of immune sensitivities in regard
to HY and HX antigens. 

COMMON MUCOSAL IMMUNE SYSTEM (CMSI): The CMSI contains
immunological cells that home to various mucosal epithelia. Many
of these cells are gamma-delta T cells, some of which are thymus-
dependent in their development, some of which are thymus-
independent. One site or origin for thymus independent T cells is
the liver. At approximately 6-8 weeks of gestational age, human
male fetuses express SRY in gamma-delta T cells in the liver
(primarily Vg9/Vd2 subset). XY-males will have been expression
HY-etc antigens from pre-implantation embryos onwards.

HORMONAL CONNECTION: The work of N Azad and colleagues (eg, Endo
133.1.215-23 1993) suggests a way the infection-induced T-cell
activation could modify hormonal expression during discrete
periods that vary from person to person (as is being considered
by Kim and colleagues re: virus events and hormonal timings). 
1.   Azad et al write "athymic mice developed hypothalamic LHRH
deficiency..."
2.   Abo et al describe an infection-induced thymus-related
process via temporary inactivation of intrathymic T cells as a
result of bacterial stimulation. (Cellular Immunol 142.125-36
1992). Fascinatingly, Abo et al also report that an opposite
process (ie, hyper-thymic activation) occurs in regard to some
viral infections.
3.   Thus, in some individuals, alterations of T-cells and/or B-
cells could co-occur with temporary alterations of LHRH and
gonadal function via a thymus/pituitary pathway. And, this kind
of alternative regulation might possibly occur in utero, because
the thymus, liver, and pituitary "come on line" in some ways by
the 2nd trimester.

                          IN CLOSING: 

These paragraphs convey a sketch of my revised hypothesis
regarding the immunological basis and mechanisms of sexual- and
gender-orientations, a treatise now amidst aggressive
preparation, soon <g?> to be a manuscript submitted. Certainly,
other topics need be addressed and are here but listed:
1. CONDITIONINGS that blend immuno-perceptions with pheromonal,
olfactory, auditory, visual, and tactile perceptions.
2. TRANSDUCTIONS whereby these various co-occurring signals
become neural events that we perceive, about which we think, in
accord with which we act.
3. COMPLEMENT & LIPOCALINS: One of the interrelated factors is
the fact that olfactory binding protein has a structure akin to
that perceived by alternative-pathway immunological complement
C8.
4. T-CELL RECOGNITION OF PHEROMONES? Some T-cells are focused to
peruse small molecules with structures that resemble pheromones
(eg, Burk et al Eur J Immunol 25.2052-58 1995 and its diagrams,
again the gamma delta T cells with Vg9/Vd2 subunits; Sieling et
al Sci 269.227-30 1995).
5. HM AND/OR TS: The immune alteration subsuming TS would
probably occur early and thoroughly, eg, during encoding of (a)
CD5+ B-cells in spanchnopleural region and (b) gamma-delta T
cells during weeks 5-9 in utero. The immune alteration subsuming
HM would have separate immune pathways and would have a focus
wherein a person's responses to others would be modified.
Probably, this kind of alternative regulation would tend to occur
later -- possibly during a neonate, toddler, or infant infection,
tho' in-utero timings are not entirely precluded for this route.
6. MOLECULAR MIMICRY & ANTI-IDIOTYPES & CROSS-REACTIVITY are
additional immunology concepts that point toward in vivo
processes by which alternative encodings of HY or not-HY might
occur, especially given the structural similarities of HY and HX.
7. EXCLUSIONS: Many of most individuals with major alternatives
of chromosomal and/or gene structure may not yield cells that fit
into the MLR patterns, because each such person's immune system
is likely to have had additional features to integrate into the
person's immunological self and sensing of others.
8. TESTABLE: Various components of these immunological processes
ought be readily testable, for instance by creating Mixed
Lymphocyte Reactions (MLRs) with cells from various combinations
of HM, HT, TS, and BI individuals. 
9. THERAPEUTICS: In some individuals with HM, identification of
T-cell and/or B-cell subsets having altered sexual expression
might allow modifications of sexual orientation -- via a
combination of (i) monoclonal antibodies that would delete the
atypical cell lines, and (ii) gene therapies based upon the
person's own stem cells coaxed to become T- and B-cells in ways
still HT.

            Teresa          April 1997        Denver
				(c)

			End of Part 3 of 3






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