CVID/Immune Deficiencies, TNF Gene Mutations, and Lyme

[ChronicLyme19]

X-memeber's post in this thread made me do some thinking:
http://www.lymeneteurope.org/forum/view ... f=5&t=5660

hv808ct wrote:
That’s why we have an immune system. Absent a functioning one, all the antibiotics in the world aren’t going to save you from a cut finger.

I also (together with late Lyme borreliosis) have immunodeficiency (CVID).

Do you think that our immune system always can "take care of" bacteria that are not killed by a short course of Doxycycline?

These are the items in which I am wondering what the relation is:

1) Out of 9 people with persistent borreliosis that I have asked so far, 7 of them have some major form of IgG, IgA, and IgM deficiency and most have been formally diagnosed with CVID. (One person hasn't been tested and one did not want to comment on their medical history). Ok, big assumption here as the sample size is tiny, but let's hypothesize that this could hold true for a decent subset of the people with persistent borreliosis.

2) The follow up comments from this study here, talking about how adding a TNF inhibitor to a previously unculturable sample post antibiotic treatment, caused the sample to become culturable.

Thread: http://www.lymeneteurope.org/forum/view ... f=5&t=5476
Anti–Tumor Necrosis Factor–a Treatment Activates Borrelia burgdorferi Spirochetes 4 Weeks after Ceftriaxone Treatment in C3H/He Mice
Heta Yrja¨ na¨ inen,1 Jukka Hyto¨ nen,1 Xiao-yu R. Song,3 Jarmo Oksi,2 Kaija Hartiala,1 and Matti K. Viljanen1
Departments of 1 Medical Microbiology and 2 Medicine, University of Turku, Turku, Finland; 3 Centocor, Inc., Malvern, Pennsylvania
http://jid.oxfordjournals.org/content/1 ... 9.full.pdf

3) When looking up info on CVID, I stumbled upon this statement:

http://ghr.nlm.nih.gov/condition/common ... deficiency

Mutations in at least 10 genes have been associated with CVID. Approximately 10 percent of affected individuals have mutations in the TNFRSF13B gene. The protein produced from this gene plays a role in the survival and maturation of B cells and in the production of antibodies. TNFRSF13B gene mutations disrupt B cell function and antibody production, leading to immune dysfunction. Other genes associated with CVID are also involved in the function and maturation of immune system cells, particularly of B cells; mutations in these genes account for only a small percentage of cases.

http://ghr.nlm.nih.gov/gene/TNFRSF13B

What is the official name of the TNFRSF13B gene?
The official name of this gene is “tumor necrosis factor receptor superfamily, member 13B.

TNFRSF13B gene mutations cause CVID in some people but do not appear to cause immune problems in others.

List of related gene changes that are associated with common variable immune deficiency:
http://ghr.nlm.nih.gov/condition/common ... ed+Gene(s)

Also included on that list is:

What is the official name of the TNFRSF13C gene?
The official name of this gene is “tumor necrosis factor receptor superfamily, member 13C.

http://ghr.nlm.nih.gov/gene/TNFRSF13C

So I wonder, if those with CVID/immune deficiencies and persistent borreliosis, happen to have genetics that make them more susceptible to Lyme? It's already known that having CVID alone makes it harder to fight off infections in general, but I wonder if there is some added role of TNF/TNF genetics that makes it even worse?

[loshakova]

I'm not sure if I've ever posted here, but I've been a member for some time. I have wondered about this too. I got sick in 2004, and was diagnosed with neuroborreliosis in 2010 with multiple positive WBs, significant vision loss, high- and low-frequency hearing loss, neuropathy, and progressive focal cognitive deficits documented with neurocognitive testing. One month later, I received a second diagnosis of Human Granulocytic Ehrlichiosis by positive ELISA. I was treated with IV ceftriaxone and IV doxycycline for 4 months, but did not respond.

I also have borderline-to-clinically-low IgM, although I have not been formally diagnosed with CVID. My IgM has actually been falling since I got sick, so it's hard not to suspect some kind of correlation.

[ChronicLyme19]

More thoughts...
I came across these two graphs in a presentation I was watching from Aucott. There is a difference in Ig response by patients that I think needs to be studied. Perhaps the etiology of these two patterns would help explain why folks develop chronic/persistent illness.

Ig Response Pattern #1

Clears.PNG (209.33 KiB) Viewed 8174 times

Ig Response Pattern #2

Chronic Lyme Igs.PNG (274.46 KiB) Viewed 8174 times

From:
https://www.youtube.com/watch?v=Qe7bf2uhXn4
(I don't' necessarily agree with everything presented, but he's the first I've seen that graphs the two different Ig responses)

My own case certainly fits pattern #2. Borderline CDC positive during the first 3 months post tick bite, relapsed after three weeks of doxycycline, and went on to watch my total globulin levels tank as the late neurological symptoms kicked in. 1.5 years in diagnosed with total IgA/IgM/IgG deficiencies, which were supposedly a life sentence according to my immunologist. After two years of antibiotic treatment my IgA/IgM deficiencies have fully resolved, and my IgG levels continue to strengthen, as do my symptoms. Many others I have asked have Ig deficiencies and yet no studies have been done in PTLDS patients studying this, only focusing on "subjective" symptoms. Ig levels are not subjective symptoms, why has no one been looking into this?

[LHCTom]

I'm curious to compare notes.

I was diagnosed with an IgG subclass deficiency of IgG1 ( 388 range of 422-1292) and IgG3 ( 30 range of 41 to 129) but my total just made the bottom of the normal range of 700-1600 at 725.

I've read where the different IgG classes appear to be targeted or predominate with different types of infections/antigens such as toxins, bacteria, viral etc..

Each IgG subclass plays a slightly different role in protecting the body against infection. Therefore, a person lacking a specific IgG subclass will be vulnerable to certain kinds of infections but not others. For example, the IgG1 and IgG3 subclasses contain antibodies against serious bacterial infections such as diphtheria and tetanus, as well as antibodies against viral proteins. In contrast, the IgG2 subclass contains antibodies against the polysaccharide coating of certain disease-producing bacteria that can cause ear and sinus infections, pneumonia, blood infections and meningitis.

The two IgG subclasses that appear to predominate in Lyme infections are IgG1 and IgG3.

I've also had extremely high levels of IL-4.

Just curious if anyone has seen IgG1 and IgG3 low and IL-4 very high routinely.

http://www.ncbi.nlm.nih.gov/pubmed/9652826

Lyme borreliosis has shown a T helper type 1 (Th1)-like immune response with high production of interferon-gamma. Since the cytokine environment seems to be important in the regulation of immunoglobulin production and in the switch between different isotypes and subclasses, and since the subclasses of IgG have different functions, we wanted to examine the IgG subclass distribution in Lyme borreliosis. We have developed an ELISA measuring flagellin-specific antibodies of the different IgG subclasses in serum and cerebrospinal fluid (CSF). Thirty-five seropositive patients with varying manifestations of Lyme borreliosis were included in the study. According to the results, the predominating subclasses in both serum and CSF were IgG1 and IgG3. In samples taken early in disease this pattern was more pronounced in patients with a subacute disease, defined as recovery within 3 months, compared to patients that later on developed chronic borreliosis. The levels of IgG2 were generally low and IgG4 was below detection level. Thus, in the IFN-gamma-predominated immune response seen in Lyme borreliosis, mainly IgG1 and IgG3 were found, i.e. the subclasses that are complement activating as well as opsonizing in humans. Increased levels of these two subclasses early in disease might contribute to recovery and counteract the development of chronicity. The absence of IgG4 is in accordance with the presumed Th1-like situation of Lyme borreliosis.

and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1542388/

Ixodes ricinus-borne borreliosis may run a protracted course. In this study we investigated the different IgG subclasses of antibodies to borreliae at different stages of the disease. In addition to the dominant subclass IgG1 and IgG3 response was found in most cases. This antibody subclass pattern with contributions of IgG2 often persists into the late stage of the disease and may last for decades. The IgG subclass response elicited by this spirochaetosis does not conform to the expected IgG4 restricted response after chronic antigenic stimulation

[Lorima]

Don't forget about Nicole Baumgarth's work (below). It isn't necessary to postulate a pre-existing immune deficit, to explain insufficient antibody levels to pass the two-tier test, or inability of antibiotics to eradicate the infection. Bb is probably quite capable of down-regulating the host immune response, as a necessary condition of maintaining the long-term infection needed to pass itself on to the next host. And its tropism for poorly perfused tissues, and long survival without reproduction, is likely to aid both immune system, and antibiotic, evasion.

I think people with healthy immune systems are quite vulnerable to LD. Some of them probably don't get terribly sick from it, just as happens with the vast majority of infectious diseases. The flu of 1918, polio, and TB are typical historical examples. Famously deadly and disabling, yes; but still the majority of cases were either subclinical, or the patients fully recovered.

It's odd how the medical community freaks out about flu and measles, but shrugs about LD.

Anticipating another IDSA defense: I see no reason to imagine that this immune suppression happens in mice but not in people. The special case of Lyme arthritis seems to be associated with antibody levels that stay high, but I suspect arthritis is a relatively rare manifestation, compared to neurological disease, in humans, even for Bbss. If that's the case, the long-lasting high IgG levels said to be usual, are instead an unusual manifestation.

Online first, July 2, 2015.

http://doi.org/10.1371/journal.ppat.1004976

Abstract

Lyme Disease caused by infection with Borrelia burgdorferi is an emerging infectious disease and already by far the most common vector-borne disease in the U.S. Similar to many other infections, infection with B. burgdorferi results in strong antibody response induction, which can be used clinically as a diagnostic measure of prior exposure.

However, clinical studies have shown a sometimes-precipitous decline of such antibodies shortly following antibiotic treatment, revealing a potential deficit in the host’s ability to induce and/or maintain long-term protective antibodies. This is further supported by reports of frequent repeat infections with B. burgdorferi in endemic areas. The mechanisms underlying such a lack of long-term humoral immunity, however, remain unknown.

We show here that B. burgdorferi infected mice show a similar rapid disappearance of Borrelia-specific antibodies after infection and subsequent antibiotic treatment. This failure was associated with development of only short-lived germinal centers, micro-anatomical locations from which long-lived immunity originates. These showed structural abnormalities and failed to induce memory B cells and long-lived plasma cells for months after the infection, rendering the mice susceptible to reinfection with the same strain of B. burgdorferi.

The inability to induce long-lived immune responses was not due to the particular nature of the immunogenic antigens of B. burgdorferi, as antibodies to both T-dependent and T-independent Borrelia antigens lacked longevity and B cell memory induction. Furthermore, influenza immunization administered at the time of Borrelia infection also failed to induce robust antibody responses, dramatically reducing the protective antiviral capacity of the humoral response. Collectively, these studies show that B. burgdorferi-infection results in targeted and temporary immunosuppression of the host and bring new insight into the mechanisms underlying the failure to develop long-term immunity to this emerging disease threat.


Author Summary

Infections with the Lyme Disease agent, Borrelia burgdorferi, often fail to generate long-term protective immunity. We show here that this is because the immune system of the Borrelia-infected host generates only short-lived, structurally abnormal and non-functional germinal centers. These germinal centers fail to induce memory B cells and long-lived antibody-producing plasma cells, leaving the host susceptible to reinfection with Bb. This inability to induce long-term immunity was not due to the nature of Borrelia antigens, as even T-dependent antigens of Borrelia were unable to induce such responses.

Moreover, influenza vaccine antigens, when applied during Borrelia-infection, failed to induce strong antibody responses and immune-protection from influenza challenge. This data illustrate the potent, if temporal, immune suppression induced by Borrelia-infection. Collectively, the data reveal a new mechanism by which B. burgdorferi subverts the adaptive immune response.


http://doi.org/10.1371/journal.ppat.1004976

Free, full text (pdf file, 3.6 MB):
http://goo.gl/oYnslx

Also see:

http://news.ucdavis.edu/search/news_det ... o?id=11254

[from Rick LaFerriere's email list:

The mission of LymeInfo is to keep you informed of issues that might be of interest to Lyme disease patients. Postings are not meant to imply that we agree with the content of all items we distribute.

For Lyme information, see:
http://www.LymeInfo.net

Please tell others how to subscribe to this group:
mailto:LymeInfo-subscribe@yahoogroups.com

[LHCTom]

Yes I have seen the work and it might help explain persisytence plus in part the ELISA and Western Blot problems given most people receive antibiotics on occasion. I was thinking the inability to produce normal levels of IgG1 and Ig3 might simply compound the issues plus impact both the ELISA which measures total B31 unbound antibodies and the Western Blot which simply separates the same antibodies into discretes bands with the optical output ( level of darknes of band) roughly measuring the quantitative level of each antigen's antibody levels. It may or may not be true that a total IgG deficiency or subclass deficiency translates into specific antigen IgG levels but seems likely.

[dlf]

ChronicLyme19, I believe I was the one who wasn't tested beyond a basic protein electrophoresis. It took two years from that initial low gamma globulin level to get another physician to retest and my gamma globulin level is still low. The reference range is 7-15 g/L and my level is 6. This time I was able to also have testing done for IgG, IgA, IgM and IgE. Of those only IgG is low. The reference range is 7.2 - 16.9 g/L. My IgG results were 5.7 g/L. The doctor did not test for IgG sub-classes, but he ordered and I recently did blood work for immune status/antibody reactivity. Specifically he wanted to see if I have antibodies to measles, mumps, rubella, diphtheria and tetanus. It will be a while before I get the results. Since my overall gamma globulin level is low, that would normally point to low IgG1 but maybe knowing if I am producing antibodies to these specific diseases will inform whether other sub-classes are involved. I had three of the above as a child and was vaccinated for the other two long ago, i.e. long before I was infected with Bb. If my low IgG is the result of infection I am not sure that this is a valid measure of whether I would make IgG antibodies to something more recent (post Lyme infection) or not. But, this is a question I will address with the doctor once I have the results, ( of course armed with the new Baumgarth study). Unfortunately, I am only booked for a follow up appointment 6 months from now, unless of course my antibody numbers seem alarming. (Nothing seems to alarm these doctors, but they aren't living in my body). I have now been on a pretty steady diet of antibiotic combinations for over 2 and a half years, so when he asked if I continue to get new infections I had a hard time to keep from laughing, but simply said that it is pretty hard to tell considering that I have been on antibiotics ever since my Lyme diagnosis and I still get periods where my symptoms get worse and my WBC and lymphocyte counts climb ever higher. Unlike most Lyme patients, I always have higher than normal lymphocytes and WBC counts that are on the high end and that climb over the reference range fairly regularly. On a positive note, he has also referred me to another hematologist.

As Lorima pointed out, I suspect Bb can cause the germinal centers problem without the need for a person to have a genetic predisposition for CVID, though certainly that would add another level of complication. Although it is not stated in the most recent Baumgarth study, I suspect the same germinal centers problem occurs even without antibiotic treatment, but I would have liked to see them actually study what happens to lymph node architecture and cellular development in the infected mice that were not treated. Maybe it was dealt with in a prior paper, I would have to go back through them with a fine-tooth comb to find what I am looking for.

In my case, there was no reason to suspect an immune problem before I had symptom onset from Lyme, so I never had a protein electrophoresis prior to infection. I rarely ever got sick. It took two years after Lyme onset and being continually sick for me to finally convince a doctor and have any immune testing done, and I am pretty sure that I had not been prescribed/taken any antibiotics between symptom onset and that test.

My albeit limited understanding is that gamma globulin protein is produced by mature germinal centers. So if the germinal centers are short-lived and are not maturing, in addition to class-switching not occurring, gamma globulin may not be produced and as a result you end up with hypogammaglobulinemia. If I am misinterpreting this, someone please set me straight.

http://europepmc.org/backend/ptpmcrende ... obtype=pdf

J Exp Med. 1957 October 31; 106(5): 627–640.
PMCID: PMC2136826
CELLULAR SITES OF FORMATION OF GAMMA GLOBULIN
L. G. Ortega and R. C. Mellors
SUMMARY AND CONCLUSIONS
The cellular sites of formation of v-globulin in lymphatic tissues of man
and in a representative human lymphoid infiltrate have been studied by
fluorescent antibody technique.
The findings indicate that 3~-globulin is formed in the germinal centers of
lymphatic nodules and in the cytoplasm of mature and immature plasma
cells of two types--those with and those without Russell bodies.
The germinal center cells that synthesize v-globulin have been designated
"intrinsic" cells to distinguish them from the medium and large lymphocytes,
and the primitive reticular cells that occur elsewhere and do not produce
v-globulin. Unlike the plasma cells, which function as individual units,
the intrinsic cells apparently form v-globulin only when they are arranged in
discrete aggregations. The function, the blood supply, and the systematic
cellular arrangement of germinal centers justifies the postulate that they are
miniature organs of internal secretion of ~/-globulin.
The release of v-globulin from its sites of formation appears to be accomplished
by holocrine and apocrine secretion. Presumably, these secretory
mechanisms are adaptations required for the production of antibody since
they have not been described in parenchymal cells that form the other serum
proteins.
The cells found to form v-globulin appear to be identical with those previously
shown to form specific antibody in response to a variety of antigens
in the experimental animal. This evidence indicates that normal v-globulin,
if it exists, originates in the same cells that produce antibody. It is suggested,
also, that each of the 3 morphologically distinct categories of cells that synthesize
~/-globulin represents a response to a particular form of antigenic
stimulation.

[ChronicLyme19]

ChronicLyme19, I believe I was the one who wasn't tested beyond a basic protein electrophoresis. It took two years from that initial low gamma globulin level to get another physician to retest and my gamma globulin level is still low. The reference range is 7-15 g/L and my level is 6. This time I was able to also have testing done for IgG, IgA, IgM and IgE. Of those only IgG is low. The reference range is 7.2 - 16.9 g/L. My IgG results were 5.7 g/L. The doctor did not test for IgG sub-classes, but he ordered and I recently did blood work for immune status/antibody reactivity. Specifically he wanted to see if I have antibodies to measles, mumps, rubella, diphtheria and tetanus. It will be a while before I get the results.

Sounds very much like my bloodwork dlf. I had globulin levels at 2.5 g/dL or above prior to the tick bite (Ref range 1.7-3.7 g/dL). Sometime between 6 months and 1.5 years in, when the nasty neurological symptoms onset, it dropped to 1.6 g/dL, just a hair below normal. More testing at the 1.5 year mark revealed IgG (low 200s Ref: 700-1600), IgM (50s Ref:50-270) and IgA (60s Ref: 80-460) as well as lack of vaccine protection from various classes of bacteria. I think the only one vaccine still held but I can't remember which one. Because of the severe low IgG levels and lack of antibodies against the classes of bacteria they started me on IVIG, then switched to sub-q Ig. They started me at 7g/week and after the first year my IgG levels were over 1000, so they let me drop a gram to 6g/week. My levels are back up over 1000 again, so I'm guessing I could drop another gram, but I'll wait to do that after I try the antibiotic pulsing. I'm curious to see if my Ig levels drop during the pulsing.

After ~2 years of antibiotics and getting my symptoms under control this was the change in levels:
IgG 200s --> 1100s (with 6g IgG supplementation)
IgM 50s --> 140s
IgA 60s --> 110s

I doubt this is even on the radar of the major immunology centers. I tried showing one of Baumgarth's other papers to my immunologist (the huge immunology dept at Mt. Sinai in NYC, supposedly one of the best immunology centers on the east coast/country). Her response was pretty much, "I haven't heard of this, but maybe. However, I'm not taking you off the Ig until you get off the antibiotics" (which I do agree makes sense). According to her, my IgM and IgA levels should have never risen either.

My albeit limited understanding is that gamma globulin protein is produced by mature germinal centers. So if the germinal centers are short-lived and are not maturing, in addition to class-switching not occurring, gamma globulin may not be produced and as a result you end up with hypogammaglobulinemia. If I am misinterpreting this, someone please set me straight.

I really think that if you have persistent lyme and low globulin or dropping globulin levels it'd be wise to get your subclasses tested as well as immune status/antibody reactivity, like dlf. My count is up to 16 people for those with chronic lyme and IgG deficiencies. Perhaps the Lyme biomarker they are so desperately searching for is the Ig levels crashing....

[ChronicLyme19]

So just an update, I've been sniffing around some CVID and hypogammaglobulinemia sites and my count is up over 30 for those who have primary immune deficiencies and persistent Lyme/co-infections from a tick bite. And those are the ones who are openly talking about it, so there must be more.

[hv808ct]

Re: CVID/Immune Deficiencies, TNF Gene Mutations, and Lyme
Post by ChronicLyme19 » Wed 12 Aug 2015 15:37

So just an update, I've been sniffing around some CVID and hypogammaglobulinemia sites and my count is up over 30 for those who have primary immune deficiencies and persistent Lyme/co-infections from a tick bite. And those are the ones who are openly talking about it, so there must be more.

Unlikely. Lyme wouldn’t even make the list of likely infections in combination with an actual immune deficiency.

Antibody deficiency and complement deficiency are associated with recurrent infections with encapsulated bacteria. These most often involve the respiratory tract, including otitis media, and may lead to bronchiectasis in childhood. Giardia lamblia infection is frequently observed in patients with combined variable immunodeficiency (CVID) or IgA deficiency.

Infections (in decreasing order of occurrence) commonly affect the upper and lower respiratory tracts (eg, sinopulmonary infections, including chronic otitis media, sinusitis, bronchitis/ bronchiectasis, pneumonia), gastrointestinal tract (e.g., bacterial or parasitic gastroenteritis), skin, joints, and meninges. Septicemia, conjunctivitis, and osteomyelitis are less common.

Encapsulated bacteria such as S pneumoniae, Streptococcus pyogenes, H influenzae, and Staphylococcus aureus are the most common pathogens. Bordetella pertussis may rarely play an important role in respiratory infections.