Lori - immunodeficiency question - IgM and IgA

[Guest guest]

Hi Lori;

I've been meaning to answer your questions for a few days now, but I

don't think I can answer all of them just yet. I've mostly read about

IgM and IgA, and know too little to comment much on IgG and IgE at

the moment; sorry!

As I inderstand it, IgM is the first immunoglobulin type to be

produced by B cells. The B cells then normally undergo immunoglobulin

isotype class switching, and in the mucosal tissue (e.g. tissue

lining the gut) the main isotype that they start producing is IgA.

This class switching from IgM to IgA requires interactions between

the T cells and B cells, and is probably also dependent upon

dendritic cells. The dendritic cells in the gut associated lymphoid

tissue produce retinoic acid which triggers the switch from IgM to

IgA production in B cells. Several cytokines may also be involved,

such as interleukin 10 and transforming growth factor beta. The

interaction between the T cells and B cells also involves proteins on

the T cell and B cell surfaces, such as CD40 and its ligand CD40L.

In any event, in normal gut tissue, IgA is produced by the B cells

(now differentiated into plasma cells) and then secreted into the gut

lumen. The secreted IgA then binds to bacterial toxins and bacterial

cell walls, keeping bacterial populations in check.

The most common type of hyper-IgM syndrome is due to a genetic defect

in the CD40L molecule, so the B cells can't interact with T cells,

and so don't make very much IgA (or IgG or IgE for that matter). They

continue to make only IgM. So these patients have high IgM, low IgA,

low IgG and low IgE. The CD40L gene is localized on the X chromosome,

and so this disease is more common in males, who have only one copy

of the X chromosome. Their deficiency in IgA makes these patients

very susceptible to gastrointestinal infections (also infections at

other mucosal surfaces where secreted IgA is important in keeping

bacteria in check). Hyper-IgM patients seem to be particularly

susceptible to sclerosing cholangitis caused by various

pathogens .... Cryptosporidium parvum seems to be the most common.

This type of sclerosing cholangitis is not usually referred to as

primary sclerosing cholangitis because it is secondary to a known

cause ... hyper-IgM syndrome and biliary tree infection.

I would not say that hyper-IgM is an " autoimmune indicator " . Rather,

I would say it is an " immune deficiency " , resulting in increased risk

of various types of infections because of a lack of IgA, IgG and IgE.

There is also a type of IgA deficiency that does not seem to involve

CD40 or CD40L. This is referred to as " isolated " or " selective " IgA

deficiency. The exact molecuar mechanisms responsible for this type

of IgA deficiency are not known, but some studies have tracked the

genetic susceptibility to isolated IgA deficiency to the major

histocompatibility complex, and some workers suggest that the

susceptibility gene (or genes) may be specific to the HLA-A1-B8-DR3

haplotype:

IMMUNOGLOBULIN A DEFICIENCY 1; IGAD1

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=137100

Most interesting the HLA-A1-B8-DR3 haplotype has also been linked to

PSC susceptibility (see for example):

s EB, Chapman RW 1999 Sclerosing cholangitis. Curr Opin

Gastroenterol. 15: 436-441. PMID: 17023986.

" Susceptibility to PSC is associated with the HLA A1-B8-DR3

haplotype "

http://www.ncbi.nlm.nih.gov/pubmed/17023986

I've mentioned before that " isolated " IgA deficiency is associated

with PSC:

Wagner A, Eichmann D 1989 Primary sclerosing cholangitis in isolated

IgA deficiency. Schweiz Med Wochenschr. 119: 835-838. PMID: 2672299.

" Primary sclerosing cholangitis was diagnosed in a patient with

isolated IgA deficiency. Similar reports in the literature suggest

that the two conditions are related. Patients with primary sclerosing

cholangitis associated with isolated IgA deficiency are distinguished

by the fact that it is mainly the intrahepatic bile ducts that are

narrowed by the fibrosing process. The disease manifests itself

comparatively early. Recurrent bouts of fever, in combination with

elevated AP, can become the leading symptom even before the onset of

jaundice. The prognosis seems somewhat more favourable than in other

patients with primary sclerosing cholangitis. "

http://www.ncbi.nlm.nih.gov/pubmed/2672299

One might expect then that if these two conditions are linked (PSC

and IgA deficiency), PSCers might have a somewhat elevated IgM? In a

recent review article by Chapman, this is in fact noted:

" Particularly common serological abnormalities are raised IgM levels

in up to 50% "

Saich R, Chapman R 2008 Primary sclerosing cholangitis, autoimmune

hepatitis and overlap syndromes in inflammatory bowel disease.

World J Gastroenterol. 14: 331-337. PMID: 18200656

http://www.wjgnet.com/1007-9327/14/331.asp

I've also mentioned that in principle, retinoic acid (vitamin A)

deficiency in the gut associated lymphoid tissue could be major

dietary factor result in markedly reduced secretion of IgA. This is

because retinoic acid produced from vitamin A by the dendritic cells

in the gut associated lymphoid tissue is required for B cells to

switch from IgM to IgA production.

Certainly PSCers seem to be commonly deficient in vitamin A (and

therefore probably retinoic acid).

So, overall, I think there are very strong ties between IgA

deficiency, and/or vitamin A deficiency and PSC.

Sorry, but I am currently at a loss as to how to explain you son's

normal IgA and IgE but low IgG and IgM.

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

>

> Hi Dave

> You have been such a great resource to everyone here, myself

included

> and I really appreciate your input on this. The recent question @

IgA

> deficiency has me wondering if there is much research out there

about

> immunodeficencies and PSC. My son Braden has low IgG and IgM and has

> not retained immunity to all but one (and minimal on the one-barely

in

> normal range) of the immunizations they have tested in his immune

> function tests. His IgA and IgE are ok.

> He was getting monthly IVIG infusions, until our insurance randomly

> decided not to pay some of the cost- but did for most months ?!?! so

> we finally (crossed fingers) have that straightened out and will

start

> again soon hopefully...

> Hyper IgM is an autoimmune indicator right ? Because IgM fights

> bacterial infections ?

> I think in my son's case the low IgG is caused by his very poor gut

> functioning- most his small bowel has been removed and he has had

> chronic and severe small bowel bacterial overgrowth problems that I

> feel were there the triggers for his PSC. He does not have

autoimmune

> problems so maybe his PSC is 'just' SC ?? I am still not clear on

why

> the 'P' is added to make it a primary and why it is considered

> secondary if there is a known source isn't the autoimmune disease

the

> known source so shouldn't it be called auto-immune sclerosing

> cholangitis then ? This is just my take on things that it is called

> secondary when there is a known source and that assumes you can

> control the known source- not the case with my son though that we

can

> control the source...

>

> I guess I am just confused on what the immune connection is and how

it

> relates to my son and if it is different for him than others with

> auto- immune disease. Any thought appreciated -even if you just want

> to tell me I am rambling and not making sense :-)

>

> Lori

> lucky mom blessed with triplets

>