Sunday, February 14, 2010
The IgM question: Is it chronic Lyme disease?
Many patients have been told by their physicians they do not have chronic Lyme disease because Western blot antibodies are in the IgM class, not the IgG class. The doctors themselves may be confused -- or adamant. The adamant ones very likely don't believe chronic Lyme exists. If you, on the other hand, believe chronic Lyme is real, you may want to discount opinions proffered by those who do not share those beliefs.
Lyme acts differently immunologically than many other germs. Patients with only IgM antibodies may have Lyme and or/ chronic Lyme. In the typical scenario of antibody response to infection the immune system makes IgM antibodies in early infection and then makes IgG antibodies in late infection. As the amount of IgG increases IgM decreases and then goes away. This is not always the case. Lyme is a clear exception to this rule.
Peer reviewed medical studies have contributed to the confusion. Selection bias inherent to published studies is one problem. The only patients selected for NIH sponsored clinical trials have had IgG, not IgM antibodies. One investigator, Brian Fallon, who treats a lot of Lyme patients, found it challenging to find patients with the 5/10 IgG band requirement; less than 5% of his patients fulfilled the study entry requirement. All studies require certain criteria for inclusion in the study. These criteria were used for standardization and in no way suggest or prove that a particular IgG response is needed for the diagnosis.
A large chunk of chronic Lyme patients have only IgM responses. Some have mixed IgM and IgG responses. In some cases IgG responses are favored and in others IgM.
Those from the no-such-thing as chronic Lyme camp stake out the position that persistent IgM responses without later production IgG antibodies represent false positive responses. Patients with only IgM responses are told that they in fact never had Lyme, or they may be told they have Lyme but it must have a new case. Science tells us something else. Some patients make only IgM antibodies. And it is known that IgM and/or IgG antibodies may persist for years after acute infection.(Steere). The CDC has not been helpful. The CDC two tier test, ELISA followed by Western Blot standard was developed for surveillance, not clinical diagnosis. The claim that the test lacks accuracy in early Lyme but is virtually 100% accurate in late stage Lyme is crazy and has no basis in science -- or published evidence. This unfounded statement unfortunately lends credence to the Lyme deniers who push the falsehood that IgM bands equal false positive.
IgeneX has published its finding that 2 specific IgM or IgG are diagnostic of the disease, stage of the illness not withstanding. Aucott has found that 20% of patients with treated acute Lyme are unable to produce IgG antibodies, likely a genetic variable. Steere published data showing persistence of IgM antibodies in late Lyme in the 1990s. This knowledge is not new. Existing literature supports the idea that certain Western Blot antibodies are highly specific for Lyme. If specific antibodies are present it is unlikely they are the product of a false positive test, irrespective of antibody class. When only IgM antibodies appear there is a alternate hypothesis. The persistence of IgM antibodies may suggest the immune system is "chronically" seeing Borrelia as an acute--new infection. This interpretation is applied by doctors in other situations. For example EBV. IgM EBV antibodies are frequently interpreted as evidence of reactivation of the infection.
Antibodies are the result of "humoral" immunity or acquired immunity. The immune system "reads" the pathogenic germ and turns the information over to the body's antibody factory. IgM and IgG antibodies are produced by the same cells: B lymphocytes. These lymphocytes may become plasma cells. The change from IgM to IgG is due to a genetically directed molecular switching mechanism. This class switching--IgM to IgG-- may not occur or occur poorly. We don't know why but these facts have been established by evidence based science.
In my experience, Lyme patients, on average, produce slightly more IgM than IgG antibodies. This may be hard to see since most IgM assays present limited data (few bands). Certain antibodies, for example: 18, 23, 31, 34, 39 41 and 93 are HIGHLY specific for exposure to Lyme bacteria and this is well described in many places.
Doctors known as LLMDs have know for decades that the IgM vs IgG class distinction does not apply to Lyme.
Addendum: Antibodies are Y shaped molecules/proteins made up of heavy chain and light chains. Some portions are variable and some portions are invariable. Binding to antigen occurs when a variable portion at the end of one leg of the Y has a structure reconfigured (controlled by gene modification). This is the part which is analogous to taking a key to hardware store to have it copied. A generic antibody is like the blank key. The key (specific antibody) is formed through a complex process. The same cells, B lymphocytes/plasma cells that make IgM antibodies also make IgG antibodies. When the class of antibody is changed it is referred to as isotopic switching. Here is the critical piece of information: the key - the variable portion of the antibody is unchanged when IgM is changed to IgG. Rather an invariant heavy chain is swapped out. Meaning: the specificity of IgM antibodies is identical to the specificity of IgG antibodies. Remember, the immune system is controlled by mediators, cytokines. The switch from one class to the next is controlled by cytokines. IgM antibodies induce cytokines which differ from those of IgG antibodies. This is why IgM and IgG antibodies have different biological properties. The cytokines communicate with different parts of the most complex system (immune system) in the body outside of the brain and the wide array of moving parts are given different tasks. IgM signals are different from IgG signals. It should all work together for the most effective killing of unwanted pathogens. The operative word is should.
Germs evolve. Germs are smart. If a pathogen can modify the signals and confuse the cells, if gives the highly motivated germ a leg up, a survival advantage, and we know that Lyme infection can modify cytokine responses. Maybe that is why isotopic switching, IgM to IgG fails for many patients.
Take home point: the part of the antibody that specifically binds to the antigen is 100% unchanged when IgM antibodies are replaced by IgG counterparts.
If you suspect you suffer with manifestations of Lyme disease only an experienced knowledgeable doctor can make the diagnosis.
Please see other BLOG posts for more information regarding this issue.