There is a mystery as to why indolent lymphomas become immunodeficient. Oh, I know about the low immunoglobulins, but it is apparent that not just CLL, but myeloma and other types of lymphoma all fail to respond well to immunization with vaccines. Response to vaccines is generally a T-cell responsibility, so what's gone wrong with the T cells?
A paper in this week's Blood addresses the problem. Reduced T cell counts are common in the untreated indolent lymphoid tumors and there is an almost universal pattern of unresponsiveness to vaccination against Hepatitis B. They identified two different patterns of dysregulation of the T-helper cell compartment.
Pattern 1: chronic immune activation with Th2 shift, in vitro hyperreactivity and T cell senescence with propensity to undergo apoptosis.
This exists in follicular lymphoma and extranodal marginal zone lymphomas. This is characterized by a marked reduction of naive T-helper cells and recent thymus emigrants. There is an activated T helper phenotype and a Th2 shift (a tendency to make IL-4 rather than IL-2). It seems that naive T cells are attracted to lymphoma sites and reprogrammed to make IL-4 by cytokines such as CCL17 and CCL22. Activated T cells (CD69+ of OX40+ T helper cells) are absent from the peripheral blood but abound at lymphoma sites. Some of these are aberrantly activated and return to the circulation where they are sensitive to activation via the TCR or CD28. These cells are prone to apoptosis. These processes act together to decrease the numbers of T helper cells available for immune reactions.
This pattern may be seen in late CLL but not in early CLL. It may also be seen in some inflammatory conditions such as SLE and rheumatoid arthritis and in some elderly persons.
The second pattern: down regulation of TCR signaling and cytokine secretion. This pattern is characterized by a reduced expression of multiple genes associated with co-stimulation of the TCR and CD28 resulting in a reduced secretion of cytokines. Among the genes under-expressed are those of the NFkappaB and PI3K pathways. A consequence of this type of T-cell dysfunction is severely impaired formation of the immunological synapse and as well as in early stage CLL it is seen in the leukemia phase of follicular lymphoma. It can be induced in normal T cells by contact with CLL cells.
There does not seem to be a role for Tregs in either pattern. Previous reports of relative increases of Tregs in indolent lymphoma, early CLL and MGUS appear to be due to an absolute reduction in naive T helper cells.
10 comments:
Terry, I don't understand the technical apects of this post, but one statement does raise an interesting question. I was diagnosed with CLL six years ago and your lab later determined it was mutated. I am asymptotic and have not had problems related to a possibly suppressed immune system. Lymphs have been up to 62 giga/l, RBC now down to 3.67 HG 103 and HCT 32. I am not sure if that is considered indolent.
A month ago I was diagnosed with arthritis - almost certainly psoriatic, i.e. an inflammatory variety.
Is there a link between these conditions and should it affect possible treatments for either?
(My GP won't put me on prednisone long term for arthritis because of the CLL.)
It is almost certainly the psoriatic arthritis rather than the CLL causing the anemia. I think that low dose methotrexate is the treatment for the arthritis.
Terry, I have MBL (36 yr old)...CD20 (mild) / CD11c (low)...total lymphocytes ranging up and down over the last 4 years from 3,200 to 4,600 (monoclonal B lymphocytes of 1,777 with the phenotype I wrote above - the only flow cytometry I had 3 years ago). My doctor says I only need total blood count yearly. I get terrified every time I read about immnunodeficiency in such disorders...would CD5- MBL cause false negative serologies? I was screened for hepatitis B and C and HIV because I got married...I got a 3rd generation ELISA assay for HIV and HCV (they only look for antibodies and do not look for virus particles)...can I trust these assays since I have MBL? I am asymptomatic.
MBL is usually not associated with immunodeficiency.
Terry, so if patients with MBL of any type (CLL-like, atypical CLL or CD5neg) are exposed to viruses like HIV or Hepatitis B/C, then regular serology (respecting window periods) is fine in your opinion?
AS far as can be determined it is. There is no indication one way or the other that MBL is associated with any immunodeficiency.
Terry, thank you...about the post above regarding "regular serology" (June 1, 2011 13:49) ...as I am not a native English speaker, what would "As far as can be determined.." mean? I am sorry and I thank you again.
No-one has done a systematic investigation into the immune competence of MBL, but what has been done suggests that it is normal.
Terry, last one, I promise (still about the question above "Regular Serology"...I only asked you what the specific phrase "As far as can be determined it is" means, not the whole sentence. I understood the general meaning of your answer. It was a problem of "language barrier". So, I would appreciate what this specific phrase "As far as can be determined it is" would be in other words. I am so sorry and embaressed to ask you that.
As far as can be determined = So far as we know.
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