Make me look stupid, please.

[Dr. Donkey]

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I'm wondering what the common sense answer is to why this thought is wrong. Type I diabetes is thought to be caused (in part, I suppose) by an autoimmune response in which antibodies target insulin-producing islet cells (???beta cells I think???). Maternal antibodies are delivered to babies through breast milk. If the autoimmune response theory is correct, why doesn't a diabetic mother pass on her disease to her baby during breast feeding? Is there a common sense answer to this question (e.g. wrong type of anitbodies)?

 

[cytoskelement]

I doubt the titer produced by breast-feeding an infant would be nearly high enough to produce the kind of damage required for DM Type I. Also, I would think that those Beta cells would regenerate quite fast after such a challenge.

 

[gschl1234]

I'm wondering what the common sense answer is to why this thought is wrong. Type I diabetes is thought to be caused (in part, I suppose) by an autoimmune response in which antibodies target insulin-producing islet cells (???beta cells I think???). Maternal antibodies are delivered to babies through breast milk. If the autoimmune response theory is correct, why doesn't a diabetic mother pass on her disease to her baby during breast feeding? Is there a common sense answer to this question (e.g. wrong type of anitbodies)?

IgA is passed through breast milk. In general, it exists as a dimer with its Fc regions bound to each other. About all they are good for is inactivation of antigens. They cannot attract killers like NK cells or macrophages (because antigen-dependent cell medicated cytotoxicity requires Fc binding and IgA's Fc's are all tied up). In summary, IgAs are able to bind via Fab region but cannot activate complement or cause any killing due to lack of free Fc. Does that help?

 

[Dr. Donkey]

👍 Very nice explanation. I appreciate the thoroughness!

IgA is passed through breast milk. In general, it exists as a dimer with its Fc regions bound to each other. About all they are good for is inactivation of antigens. They cannot attract killers like NK cells or macrophages (because antigen-dependent cell medicated cytotoxicity requires Fc binding and IgA's Fc's are all tied up). In summary, IgAs are able to bind via Fab region but cannot activate complement or cause any killing due to lack of free Fc. Does that help?

 

[gschl1234]

But your question does bring something else into mind. IgG passes freely through the placenta. Why don't beta cells of pancreas get destroyed during development? A guess would be that mom's beta cell epitopes are different enough from fetal beta cell epitopes so there's no recognition in the Fab region. Any thoughts?

 

[bioteacher]

Are antibodies even absorbed into the bloodstream of the babies through the breast milk? I would think proteins of this size wouldn't even make it in.
I would also think that they would be denatured by the stomach acid (unless they really are absorbed while in the mouth and throat).

 

[v-tach]

Are antibodies even absorbed into the bloodstream of the babies through the breast milk? I would think proteins of this size wouldn't even make it in.
I would also think that they would be denatured by the stomach acid (unless they really are absorbed while in the mouth and throat).

IgA's are generally found in places like mucous membranes (such as those of the gut!), not in the bloodstream. I'm pretty sure they are able to withstand the stomach acid--they end up in the epithelia of the GI tract.

 

[Persistence101]

I'm wondering what the common sense answer is to why this thought is wrong. Type I diabetes is thought to be caused (in part, I suppose) by an autoimmune response in which antibodies target insulin-producing islet cells (???beta cells I think???). Maternal antibodies are delivered to babies through breast milk. If the autoimmune response theory is correct, why doesn't a diabetic mother pass on her disease to her baby during breast feeding? Is there a common sense answer to this question (e.g. wrong type of anitbodies)?

In addition to the other explanations, it wouldn't be an autoimmune disorder because those are the mother's antibodies, not the baby's. To get the disorder, the baby would have to make his own antibodies against his own beta cells.

 

[liverotcod]

IgA is passed through breast milk. In general, it exists as a dimer with its Fc regions bound to each other. About all they are good for is inactivation of antigens. They cannot attract killers like NK cells or macrophages (because antigen-dependent cell medicated cytotoxicity requires Fc binding and IgA's Fc's are all tied up). In summary, IgAs are able to bind via Fab region but cannot activate complement or cause any killing due to lack of free Fc. Does that help?

Oh. My. God.

I am so not ready for medical school. Does this kind of stuff come up in ordinary conversation?

 

[hakksar]

Also there is quite a bit of evidence from the Barbara Davis Center (a large Type 1 diabetes research center here at CU) that much the autoimmune destruction of the beta cells is from Killer T Cell destruction of the beta cells and not from antibody reactions. Therefore, since the mother only has IgA antibodies in her breast milk (and not any Killer T Cells) there is not really any mechanism for the mother's breast milk to kill the beta cells.

http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=15622961

 

[gschl1234]

Are antibodies even absorbed into the bloodstream of the babies through the breast milk? I would think proteins of this size wouldn't even make it in.
I would also think that they would be denatured by the stomach acid (unless they really are absorbed while in the mouth and throat).

Great point! I wasn't even thinking about that! You're totally right. The only way it could be transported would have to be via endocytosis and as far as I know, the GI tract doesn't have receptors for it going in that direction. I think my prof said that IgA doesn't become inactivated in the stomach because it ends up in the small intestine and colon of the baby. It's protective since it takes a while for baby to build up normal flora in the gut.

 

[jennie 21]

Also, high levels of autoimmune antibodies to beta cells are only present during the initial stages of Type I diabetes, when the beta cells are actively being destroyed. Assuming the mother has had the disease for awhile (a fair assumption since Type I diabetes usually develops during childhood or adolescence) she wouldn't have high enough titers of anti-islet-cell antibodies in her blood to do the baby any harm, I think, via passage of the antibodies through the placenta. She probably still has a few memory B-cells around that encode antibodies to islet cells, but she isn't actively producing anti-islet-cell antibodies after she's had the disease for a few years and the islet cells are all destroyed (i.e., you need antigen stimulation to stimulate antibody production, or we'd all be constantly making antibodies to every antigen we'd ever encountered). Anyway...that's my guess as to why the baby's islet cells aren't destroyed by IgG antibodies crossing the placenta. Mom probably only has very low anti-islet-cell antibody titers, if she has any at all.

 

[hakksar]

Also, high levels of autoimmune antibodies to beta cells are only present during the initial stages of Type I diabetes, when the beta cells are actively being destroyed. Assuming the mother has had the disease for awhile (a fair assumption since Type I diabetes usually develops during childhood or adolescence) she wouldn't have high enough titers of anti-islet-cell antibodies in her blood to do the baby any harm, I think, via passage of the antibodies through the placenta. She probably still has a few memory B-cells around that encode antibodies to islet cells, but she isn't actively producing anti-islet-cell antibodies after she's had the disease for a few years and the islet cells are all destroyed (i.e., you need antigen stimulation to stimulate antibody production, or we'd all be constantly making antibodies to every antigen we'd ever encountered). Anyway...that's my guess as to why the baby's islet cells aren't destroyed by IgG antibodies crossing the placenta. Mom probably only has very low anti-islet-cell antibody titers, if she has any at all.

From my understanding IgG doesn't pass through the placenta at all, but I might be mistaken (I thought that the placenta was a barrier to the mothers immune system so that the mother does not destroy the fetus which would be foreign to the mother which is why there is not destruction of the fetus when the fetus is an AB bloodtype and the mother is only A or B)

 

[IllinoisStudent]

I don't think IgA would cause any harm to the baby because of the two reasons discussed above.

IgG does cross the placenta, and IgG can cause Antibody Dependent Cell Cytotoxicity (ADCC) with NK cells. I think T cells would not induce apoptosis in Beta cells because they are not activated in fetus. So I will take CTL mediated cell toxicity out of question here. I did a quick search on potential problems in pregnancy among women with Type 1 diabetes. I didn't find any mention of beta cells dying in the fetus. So I would assume that Beta cells are not harmed (or not significantly harmed) in fetus (<--Disclaimer: This assumption can be wrong). Using deductive logic, it would be safe to conclude that NK cells are not activated in fetus and so there is no ADCC in Beta cells. In addition, detection of MHC I on the target cell sends a 'don't kill' signal to NK cells. So baby's Beta cells might be safe afterall.

 

[hakksar]

Actually, I have been to 8-10 seminars recently that have demonstrated that CTL's do cause apoptosis in Beta cells in human studies and this is increasingly being recognized as one of the major immune mediators of beta cell destruction in Type 1 DM (I am too lazy to look up the papers which is why I just attached an old review abstract from pub-med discussing the topic). As for IgG passing the placenta how is the fetus protected from maternal IgG destruction then? Since an AB blood type fetus is not destroyed by maternal antibodies and almost cerrtainly the mother would have antibodies to either the A or B sugar (since they are very close to if not the same as those on many bacteria that resides in the gut flora) how come the IgG's do not kill the fetus?

edit: I know the beta cells are safe since there are many studies here at CU where Type 1 DM mothers have had babies and the risk for the offspring developing Type 1 DM is actually lower in mothers with Type 1 DM then fathers with Type 1 DM. If there was maternal destruction of beta cells in a fetus with a type 1 mother this would almost certainly be reversed.

 

[pratik7]

IgA autoantibodies are actually quite rare. IgM is by far the most common type of autoantibody followed by IgG.

 

[gschl1234]

IgA autoantibodies are actually quite rare. IgM is by far the most common type of autoantibody followed by IgG.

Serum IgA is rare. But the most abundant Ig on your body is IgA (mucous membranes = huge surface area). If you grind up a person and analyzed for Igs, you'd get A>G>M.

 

[DrChandy]

In addition to the other explanations, it wouldn't be an autoimmune disorder because those are the mother's antibodies, not the baby's. To get the disorder, the baby would have to make his own antibodies against his own beta cells.

Precisely,
The antibody in question produced by the mother is specific to her genetic makeup and the expression of her genome, and thus specifically reacts to an epitope present on a specifically expressed surface protein present on her pancreatic islet beta cells. The infant may elicit an 'autoimmune' (quoted, as passive immunity is implied [versus active] in such a scenario) response only if he/she expresses the same homologue of the protein on his/her islet beta cells, and receives the antibody from the parent. If the infant, therefore, inherits the means of expressing both the antigenic protein and the specific antibody from the mother through his/her beta cells and B plasma cells respectively, he/she may develop symptoms similar to the parent.

 

[IllinoisStudent]

Actually, I have been to 8-10 seminars recently that have demonstrated that CTL's do cause apoptosis in Beta cells in human studies and this is increasingly being recognized as one of the major immune mediators of beta cell destruction in Type 1 DM.

If this is in reference to my post, I was talking about fetal T cells, not T cells in mom. CTLs do cause apoptosis in islet beta cells in mom.

Serum IgA is rare. But the most abundant Ig on your body is IgA (mucous membranes = huge surface area). If you grind up a person and analyzed for Igs, you'd get A>G>M.

ditto. to the point.

Precisely,
The antibody in question produced by the mother is specific to her genetic makeup and the expression of her genome, and thus specifically reacts to an epitope present on a specifically expressed surface protein present on her pancreatic islet beta cells. The infant may elicit an 'autoimmune' (quoted, as passive immunity is implied [versus active] in such a scenario) response only if he/she expresses the same homologue of the protein on his/her islet beta cells, and receives the antibody from the parent. If the infant, therefore, inherits the means of expressing both the antigenic protein and the specific antibody from the mother through his/her beta cells and B plasma cells respectively, he/she may develop symptoms similar to the parent.

Good point, but the immune system attacks insulin, Glutamic acid Decarboxylase (GAD) and protein named IA-2 among others. It seems the immune system is targeting molecules that are unique of islet Beta cells (hence, selective killing of Beta cells). I am not sure if genetic make up makes a significant difference because some of these molecules might be same in all humans.

On a second thought, jennie 21's argument about absence (or negligible presence) of IgG might also explain the survival of Beta cells in fetus, assuming that Beta cells do indeed survive in the fetus.

 

[Doc Ivy]

To clarify: IgG crosses the placenta... IgM does not.

Since as someone pointed out most autoantibodies are IgM and not IgA this entire discussion become moot

 

[kyriacos01]

To clarify: IgG crosses the placenta... IgM does not.

Since as someone pointed out most autoantibodies are IgM and not IgA this entire discussion become moot

As previously stated, IgA autoantibodies are quite rare; however they, and more significantly IgG, are not moot. IgA, combined with IgG and IgM or independently, can mediate autoimmune hemolytic anemia. Since there is no commercially available IgA standard, most diagnostic laboratories frequently fail to detect erythrocyte or serum antigens; accordingly, patients are often diagnosed with non-specific Coomb's negative anemia.

Moreover, AIHA disorders may occur irrespective of hemolysis. Alone, direct antigen testing does not confirm autoimmune hemolytic anemia; i.e., +IgG warm dat may also be associated with delayed or acute transfusion reaction or drug induced hemolyis; +IgM cold dat is most often indicative of C3 binding; while –IgG/IgM dats may suggest Thalassemia, Sickle cell anemia, DIC, PNH, TTP, etc.

In general, IgG has a greater clinical significance in the detection of most chronic auto/allo antibodies while IgM applies to the detection of acute auto/allo antibodies. Also, a large proportion of IgM testing has little significance in vivo. Regardless of the method of detection and with respect to the variability among patients, there persists a state of clinical ambiguity surrounding the etiology of most disorders. Therefore, a significant number of methodologies (IgG, IgM, and IgA auto/allo antibody detection) may be utilized.


All the best,
-ky

 

[Doc Ivy]

I completely agree with you that IgG erythroblastoses (and other conditions mentioned) are important clinical consequences of alloimmunity.

However, the original question was about autoimmunity, and the possibility that a Type 1 DM mom could pass her IgM beta cell autoantibodies to her fetus and thus cause "vertical' transmission of diabetes. This is just impossible for so many reasons.

 

[Dr. Donkey]

I made a test question.

 

[kyriacos01]

...the possibility that a Type 1 DM mom could pass her IgM beta cell autoantibodies to her fetus and thus cause "vertical' transmission of diabetes. This is just impossible for so many reasons.

Agreed; cheers, love.

All the best,
-ky

 

[jennie 21]

On a second thought, jennie 21's argument about absence (or negligible presence) of IgG might also explain the survival of Beta cells in fetus, assuming that Beta cells do indeed survive in the fetus.

Actually, that was not my argument. There are a significant amount of IgG antibodies from the mother that cross the placenta. My argument was that the specific antibodies against the islet cells would no longer be present in significant quantities, because given that all the mother's islet cells would have long since been destroyed in the early course of Type 1 diabetes, there would be no antigen (i.e. islet cell antigen) around to stimulate production of antibodies by the memory B-cells in the mom that encode antibodies against islet cells. There are plenty of other IgG antibodies that will get passed along to the baby through the placenta; but it is highly unlikely that the mother would have significant titers of anti-islet-cell antibodies in the absence of antigenic stimulation, years after all of her own islet cells have been destroyed. No beta cells=no antigen=no anti-beta-cell antibodies in the mom's blood at the time of her pregnancy.

The only way I could see the baby's islet cells being destroyed by the mom's antibodies would be in the rare condition that she developed Type 1 Diabetes for the first time while she was pregnant. In that case, there would be significant titers of circulating IgM and IgG antibodies against the islet cells in her blood, and the IgG antibodies could theoretically cross the placenta and be passed along to the baby. Even then, I'm not sure if her antibodies would destroy the baby's beta cells because 1)they might be different epitopes so mom's antibodies would not necessarily bind to baby's islet cells and 2)the baby doesn't have an efficient killer-T system in place yet, and since cytotoxic T-cells appear to be involved in destruction of beta cells in diabetes, if the baby doesn't have mature cytotoxic T-cells in utero (which I don't think it would) then even if the anti-islet-cell antibodies were present it wouldn't induce killing of the beta cells by the baby's immune system because the baby lacks cytotoxic T-cells which would induce apoptosis of the beta cells. I remember learning something second year about how infants don't have an efficient killer-T-cell response which is the reason they're more likely than adults to develop chronic Hepatitis B infection if they contract Hepatitis B, while most adults can manage to clear the virus because of their cytotoxic T-cell response. I could be confused about that, though.

Anyway, my main point was that if the mother has had diabetes for a number of years then 1)all of her islet cells have already been destroyed so therefore 2)there wouldn't be any antigen (i.e. islet cells) left around to stimulate antibody production by anti-islet-cell B cells and since B cells don't continue to produce antibodies in the absence of antigenic stimulation (they require antigenic stimulation to continue producing antibodies, in the absence of stimulation by antigen activated B-cells will undergo apoptosis fairly quickly), she would not have titers of anti-beta-cell antibodies present in her blood in significant amounts at the time of her pregnancy. I don't know if my explanation makes sense, but that's what I think.

 

[ERMudPhud]

I finally got around to doing a quick lit search on this and here is your answer.

J Clin Endocrinol Metab. 2001 Oct;86(10):4826-33. Related Articles, Links

Prevalence, characteristics and diabetes risk associated with transient maternally acquired islet antibodies and persistent islet antibodies in offspring of parents with type 1 diabetes.

Naserke HE, Bonifacio E, Ziegler AG.

The main points here are that mothers DO transmit their autoantibodies to their babies in utero even if they have had diabetes for some time but the children generally don't get diabetes. The paper is a bit difficult to follow because you have to realize that as first generation relatives of patients with type 1 diabetes the kids are already at risk for insulitis and diabetes. They control for this by comparing children of type 1 fathers to children of type 1 mothers and showing significantly more autoantibodies in the babies of type 1 mothers. They then follow the children from type 1 mothers and show that most of them gradually lose autoreactivity. These are the ones that just got passive tranfer of autoantibodies. They also fail to show development of isotypes or specificities beyond what was transfered by the mother thus indicating they have no ongoing immune response to islet cell antigens. The others show persistance of autoantibodies, class switching, affinity maturation, and antigen spread eventually developing diabetes. These are the ones that are probably going to get diabetes anyway because of their unlucky genes (certain HLA types etc...) and the presence of autoantibodies in them at 9 months is more an early marker of disease onset rather than a sign of maternally transferred antibodies. So how do we reconcile this with the previous discussion along with clearing up a few errors

1. Maternal IgG including autoreactive (or more accurately anti islet cell) IgG is tranferred to the offspring. The epitopes generally recognized by autoantibodies in diabetes(insulin , glutamic acid decarboxylase antibodies, and tyrosine phosphatase IA-2) are well conserved and should be present in all offspring regardless of what genes they inherited from the parents. These transferred antibodies do not however contribute to disease.

2. Anti islet cell reactivity persists in mothers even with long standing disease. I'll find a reference more specific than the above one later. This occurs for several reasons. First, a primary source of circulating IgG is plasma cells which have lost surface immunoglobulin expression and are thus no longer antigen responsive. A subset of them are very long lived (measured in years) and will thus continue to pump out antibody in the absence of antigen. Furthermore just because the islet cells are gone doesn't mean the antigens are gone. Glutamic acid decarboxylase and tyrosine phosphatase IA-2 are, I believe, not islet cell specific in their expression and insulin is still being provided exogenously.

3. The primary reason the babies don't get disease is because although anti islet cell antibodies are an excellent early marker of diabetes they are not necessarily causitive. They may in fact be an effect of the disease, destruction of islet cells releases hidden islet cell antigen which then stimulate antibody production. A well studied mouse model of autoimmune diabetes is the NOD mouse. T cells are absolutely required for disease in this mouse and since autoreactive T cells can't cross the placenta the child would need to develop them on their own in order to get disease. Interestingly, in the NOD mouse B cells are required as well for the disease but they don't have to be autoreactive B cells. The B cells may be serving more of an antigen presentation function in this case rather than the manufacture of autoantibodies

 

[ERMudPhud]

Two things I forgot to add

1. In humans IgG does not get absorbed by the baby from breast milk because human intestinal epithelial cells lack the right Fc receptor but a significant amount crosses the placenta and persists for many months in the neonatal serum. Many other animals can absorb IgG from milk. Interestingly, pigs get no transplacental antibody and get it all from milk


2. The IgA in human milk is also minimally absorbed by the baby but instead serves to provide passive mucosal immunity

 

[kenshinoro2004]

IgG is passed through the placenta (BRS Immuno pg. 222, except subclass IgG4). IgM does not. DM is caused by both cell mediated and humoral immunity (most likely one or the other in a given patient). So, if the IgG's did recognize the Beta cells, they could kill them, but the antibodies would run out after a few months post birth (as seen a with positive Coombs test's at birth, and then negative months later). Those targeted Beta cells would likely be killed, but new ones would take their place and no more antibodies would remain to kill them, since the child would not be the source of the antibodies, it would be like a passive immunization.

 

[emusibay]

Hey guys, just wanted to say that I appreciate the discussion. As a working Immunologist researcher transitioning to medicine, I feel proud of you all and of our chosen profession.

 

[thackl]

Oh. My. God.

I am so not ready for medical school. Does this kind of stuff come up in ordinary conversation?

No, and most of it's forgotten until step1, then again until you actually have to use it. Don't let the gunners freak you out and definitely don't listen to your classmates at school (it can be quite stressful). A lot of them (not all) will grandstand about the little pieces on minutia they know just to intentionally freak people out. It worked a little on me the first block down at the old anatomy lab....... but guess who's sitting at the top.... not them!

BTW, this is not an attack on the current thread. You guys are having an interesting and meaningful discussion. I had honesly forgotten some of this from biochem, but have to relearn it next yr. Just trying to keep the newbie from getting stressed 🙂