IVIG: Tolerance and Depletion of B Cells.

Remy

Administrator
I thought this was pretty interesting...most of us are used to hearing about IVIG (intravenous immunoglobulin replacement) simply as a booster for those of us with low levels of immunoglobulins.

But there has been a lot of chatter and speculation that IVIG may work well for other autoimmune and inflammatory disorders. I haven't seen a lot of research on this topic though which is why I found the following so interesting.

Basically what they are saying is that IVIG seems to induce tolerance by rendering them unable to respond to this antigen driven BCR signaling. The B cells stop (over) reacting to the antigenic stimulation and enter a state of anergy.

Beyond that, IVIG seems to induce a state of B cell depletion through apoptosis (programmed cell death). Isn't that what Rituximab purports to do?

Bottom line is, though, that insurance companies are unlikely to take notice until a lot more research is done given the high cost of IVIG/SCIG. The best bet would be to try to get diagnosed with a standard immunodeficiency disease if one wants to try IVIG and have it covered by insurance.

Full text here.

Dussault et al. demonstrated on human B-cell lines that immunomodulation of human B-cells following treatment with IVIG involves increased phosphorylation of ERK and also Grb2- associated binder 1 and Akt, thus influencing BCR signaling (35). Other studies demonstrated that IVIG in vitro induces apoptosis of human B-cells through a Fas- and caspase-dependent pathway (36, 37).

Besides this mechanism J. F. Séité and his group demonstrated that modulation of ERK activation in B-cells by IVIG ligation with CD22 is associated with cell-cycle arrest at the G1 phase and B- cell apoptosis (see above) (8).

More recently, they showed that in vitro IVIG treatment of B-cells renders them refractory to BCR stimulation, suppresses the PI3K signaling pathway, and induces a long-term state of tolerance, promoting a program of long-term functional silencing similar to anergy (38).

High-constitutive ERK phosphorylation is a central feature of murine models of anergy driven by constant BCR occupancy by antigen (39); in these aner- gic B-cells, constitutively activated ERK provides a tolerogenic signal dampening TLR-9 responsiveness (40). We showed that a subpopulation of human B-cells characterized by the reduced expression of CD21 (CD21low B-cells) closely resemble murine anergic B-cells (41). CD21low B-cells are expanded in a subset of patients with common variable immunodeficiency (CVID) and in some other immunological disorders and are characterized by high-constitutive ERK activation (41), low responsiveness to TLR- 9 and BCR stimuli (42, 43), and propensity to apoptosis (44).

In this regard, we observed that IVIG replacement therapy in CVID patients profoundly affects B-cell homeostasis (41).

To investigate whether IVIG modulates in vivo ERK signaling in B-cells from CVID patients, we analyzed constitutive and BCR-induced ERK phosphorylation before and after IVIG infusion.

We showed that unstimulated naive and IgM+ memory B-cells have significantly increased constitutive ERK activation after IVIG infusion, whereas BCR-induced activation, expressed as the fold increase respect to the constitutive ERK level, decreased in these cells (41).

More recent observations from our group showed that IVIG infusion induces in vivo selective B-cell depletion in CVID patients. This effect is preceded by a profound modulation of B-cell homeostasis, where IVIG induces the down-regulation of CD21 expression pro- moting the generation of anergic-like, apoptosis prone CD21low B-cells. We found that these newly generated CD21low B-cells displayed the same peculiar pattern of receptors expressed by CD21low B-cells present before IVIG, namely, increased FCRL4 and CD11c, and reduced CD62L expression (45).

In addition, these newly generated CD21low B-cells, upon overnight culture, undergo spontaneous apoptosis. These obser- vations suggest that IVIG therapy in vivo, even at a replacement dosage, may influence antibody responses by inducing B-cell depletion through differentiation into CD21low B-cells that undergo accelerated apoptosis (45).

Bayry et al. demonstrated that IVIG in vitro at low doses induced proliferation and immunoglobulin synthesis from B- cells of CVID patients. It seems that IVIG rectifies the defective signaling of B-cells normally provided by T cells and delivers T- independent signaling for B-cells to proliferate (46). Moreover, in accord with our data, they showed that IVIG at low does induced the phosphorylation of ERK 1/2, Akt, and p38 MAPK in B-cells of CVID patients.

In conclusion, all these observations suggest that IVIG therapy in CVID patients, in particular, in those with autoimmune man- ifestations, may not only replace the missing antibodies but also regulate autoimmune and inflammatory responses through the modulation of B-cell functions (46).
 

Who Me?

Well-Known Member
I'm going through that right now @Remy First :asshat: allergist wouldn't diagnose. 2nd :asshat: said hypogammaglobulinemia but wanted me to have a psych eval and finally an actual real live Clinical Immunologist has diagnosed me with CVID. I think that surprised him since I don't have a history of infections.

Next week I'm getting more labs done, one for autoimmune disorders, I'm totally blanking on the other but it's the one with CD8 etc and then pre vaccine challenge labs. And pneumovax 23. Then a month later post pneumovax labs.

After that we will see. We talked about IVIG before he saw the labs and said I had to have 2 documented by CT bacterial infections to get it.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
I thought this was pretty interesting...most of us are used to hearing about IVIG (intravenous immunoglobulin replacement) simply as a booster for those of us with low levels of immunoglobulins.

But there has been a lot of chatter and speculation that IVIG may work well for other autoimmune and inflammatory disorders. I haven't seen a lot of research on this topic though which is why I found the following so interesting.

Basically what they are saying is that IVIG seems to induce tolerance by rendering them unable to respond to this antigen driven BCR signaling. The B cells stop (over) reacting to the antigenic stimulation and enter a state of anergy.

Beyond that, IVIG seems to induce a state of B cell depletion through apoptosis (programmed cell death). Isn't that what Rituximab purports to do?

Bottom line is, though, that insurance companies are unlikely to take notice until a lot more research is done given the high cost of IVIG/SCIG. The best bet would be to try to get diagnosed with a standard immunodeficiency disease if one wants to try IVIG and have it covered by insurance.

Full text here.
That is really interesting....I believe that is exactly what Rituximab is supposed to do....and one reason they believe it does that in ME/CFS is that it takes several months to see an effect.
 

Hope

Active Member
I've been so wondering how IVIG affects B cell issues, this is so timely, thanks @Remy. I've had 8 months of IVIG, 2 more left. Haven't noticed any change in symptoms sadly...
 

Hope

Active Member
Low sub groups of Ig's plus chronic infections, the usual culprits. The immunologist hesitated a lot and I was surprised when he finally agreed to it.
 

Who Me?

Well-Known Member
Low sub groups of Ig's plus chronic infections, the usual culprits. The immunologist hesitated a lot and I was surprised when he finally agreed to it.
My immuno (before labs) wouldn't discuss it because I have not had infections. Labs come back with low total IgG, low subsets 1 &3 low IgA and high IgM. He changed my DX from another doc from hypogammaglobulinemia to cvid. Next week more labs for auto immune stuff, lymphocyte subsets and pre pneumovax 23 vaccine challenge.
 

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