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Got Protection? Immunoglobulins

Date: June 8, 2024

Immunoglobulins (“Ig” for short) are a very important part of our defenses against most bacteria and some viruses as well. They are even more important when we consider CLL patients have defective B-cells (heck, this is, after all, a cancer of the B-cells); and since B-cells and T-cells hang out together, there is a lot of research suggesting T-cells are compromised as well. Take away B-cells, T-cells and immunoglobulins, there is not much left to protect us against the pathogens out there. Talk about the perfect storm!

Why do CLL patients have low immunoglobulin levels? Well, for starters, Igs are made by plasma cells, which in turn come from mature, healthy B-cells. Got no healthy B-cells? Say good-bye to plasma cells, as they die off gradually over time. No plasma cells? Forget about replacing immunoglobulins as they are gradually chewed up over time. This much we knew already: it is the reason why Ig levels gradually decrease in CLL patients over time.

What is new is the latest article in Blood Journal. This paper reports that there is a variety of plasma cells that are unusually long lived. These plasma cells hang out in the tonsils. Their long-life may explain why Ig levels drop slowly in CLL patients, sometimes taking years to hit bottom. But what about CLL patients treated with Rituxan? Guess what folks, these precious, long lived plasma cells, the source of the few small hordes of immunoglobulin molecules we can make, these plasma cells carry the tell-tale CD20 marker that is the target of Rituxan therapy. In other words, while you go after the nasty CLL cells with their CD20 markers during "targeted" Rituxan therapy, you are also killing off the last remaining long lived plasma cells. Ouch indeed.

Another interesting bit in this article: Campath therapy is no better either. Campath goes after CD52, the marker that is expressed by all B-cells, T-cells, neutrophils, monocytes, etc. No wonder patients are very immune suppressed after Campath therapy, with so many important immune system cells targeted. This is the thud as the second shoe drops. T-cells provide “live long and prosper” survival signals to the long-lived plasma cells safely tucked away in the tonsils. With no T-cells murmuring soothing and encouraging survival signals, pretty soon all the plasma cells in the tonsils curl up their toes and die en masse. When all the plasma cells are gone, and no new ones are being made because there are so few healthy and mature B-cells, you can see why you have no way of making your own immunoglobulins.

What is the solution, short of curing CLL? Get intravenous immunoglobulin (IVIg) therapy. Easier said than done. Immunoglobulins are very expensive and often in short supply. Doctors are reluctant to prescribe IVIg therapy — and insurance companies hate to pay for it. You can read more about it in our review article (Benefits of IVIg Therapy) published a while ago. But remember, in cancer therapy as in life, you get pretty much what you negotiate. Fairness seems to have very little to do with it.

Be well,

Chaya
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Abstract:

Blood Journal Abstract. 2024 Jun 1;109(11):4856-64.

T cell-dependent survival of CD20+ and CD20- plasma cells in human secondary lymphoid tissue.

Withers DR, Fiorini C, Fischer RT, Ettinger R, Lipsky PE, Grammer AC.

The signals mediating human plasma cell survival in vivo, particularly within secondary lymphoid tissue, are unclear. Human tonsils grafted into immunodeficient mice were therefore used to delineate the mechanisms promoting the survival of plasma cells. Tonsillar plasma cells were maintained within the grafts and the majority were nonproliferating, indicating a long-lived phenotype. A significant depletion of graft plasma cells was observed after anti-CD20 treatment, consistent with the expression of CD20 by most of the cells. Moreover, anti-CD52 treatment caused the complete loss of all graft lymphocytes, including plasma cells. Unexpectedly, anti-CD3, but not anti-CD154, treatment caused the complete loss of plasma cells, indicating an essential role for T cells, but not CD40-CD154 interactions in plasma cell survival. The in vitro coculture of purified tonsillar plasma cells and T cells revealed a T-cell survival signal requiring cell contact. Furthermore, immunofluorescence studies detected a close association between human plasma cells and T cells in vivo. These data reveal that human tonsil contains long-lived plasma cells, the majority of which express CD20 and can be deleted with anti-CD20 therapy. In addition, an important role for contact-dependent interactions with T cells in human plasma cell survival within secondary lymphoid tissue was identified.

PMID: 17299094
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