carole - phagocytosis of treponema under penicillin tx

[Guest guest]

Carole, heres the one I mentioned. I'm not sure whether they

actually saw the phagocytosis or merely inferred it from the loss of

detectability of the organisms.

I would note that not everything published is right, and these folks

assertion that the treponemes were intracellular might attract

controversy amongst treponemologists, tho there are at least some

authors who are convinced treponemes can be intracellular (its not

very straightforward to tell on an electron micrograph whats

happening in the hieght/depth dimension).

Anyway, the rapid loss of the organisms detectability means they

either changed form/position to become unrecognizable, or else were

destroyed, which latter would tend to justify our picture of the J-H

reaction as being caused by liberated bacterial molecules. I forget

what phases of syphilis the JHR occurs in, but this phase (primary)

is evidently curable, suggesting that the organisms were destroyed

rather than made unrecognizable. In contrast, in neurosyphilis (a

tertiary phase form) symptoms often persist after treatment, and I

dont think anyone really knows whats happening. (If the disease

could progress after treatment, I would conclude that the infection

is not eradicated; but so far I havent heard that it does.)

===========================================

Treponema Pallidum in early syphilitic lesions in humans during high-

dosage Penicillin therapy

An Electron Microscopical Study

J. Wecke1, J. Bartunek2 and G. Stüttgen2

(1) -Koch-Institute, Berlin, Germany

(2) Department of Dermatology of the Free University of Berlin,

Rudolf-Virchow-Hospital, Augustenburger Platz 1, D-1000 Berlin 65,

Germany

Received: 8 September 1976

Summary The alterations of early syphilitic infection occuring in

the course of high dosage penicillin (120 mega IU, 36 h) as clinical

experimental trial has been studied both from the clinical and the

electron microscopical views.

By electron microscopical studies, findings revealing the

localization and the status of treponemes before and during

penicillin treatment could be established. Before treatment started,

the majority of treponemes was of intercellular localization. In the

course of treatment various forms of destruction could be

differentiated. The most striking change in the host tissue after 7–

8 h of penicillin therapy was an elimination of treponemes by

penetrating phagocytes. 24 h after the beginning of treatment,

treponemes could not be demonstrated any more. The clinical and

serological findings after the high dosage penicilline will produce

results comparabel to those of conventional therapie.

[Guest guest]

Hello ,

Ok, am trying to understand. See if my logic holds : JHR is seen with penicillin treatment of syphillis. In the case of this study, high-dose pencillin rapidly rendered any treponemes undetectable. If we assume they were killed (which is likely in early stage infection, likely because we know that stage 1 is curable ?) and that the patients suffered JHR in this study (again likely ?), then the JHR experienced would be due (at least in part) to the effects of the dead or dying treponemes. Would be more convincing with a few less assumptions...

Seems like there may also be evidence of cytokine mediation. I found a reference to a 1996 study, "Prevention of Jarisch–Herxheimer Reactions by Treatment with Antibodies against Tumor Necrosis Factor ", Fekade, M.D., Knox, M.B., Kebede Hussein, M.B., Amsel Melka, M.B., G. Lalloo, M.D., Ruth E. on, F.I.M.L.S., and A. Warrell, D.M.

The conclusion given in the abstract (don't have access to the full article) states that pretreatment with a sheep anti–TNF- Fab suppresses the JH reaction in cases of louse-borne relapsing fever (borrelia recurrentis) : http://content.nejm.org/cgi/content/full/335/5/311.

Do you have an opinion on this, ?

Carole

> Carole, heres the one I mentioned. I'm not sure whether they actually saw the phagocytosis or merely inferred it from the loss of detectability of the organisms. > Anyway, the rapid loss of the organisms detectability means they either changed form/position to become unrecognizable, or else were destroyed, which latter would tend to justify our picture of the J-H reaction as being caused by liberated bacterial molecules. I forget what phases of syphilis the JHR occurs in, but this phase (primary) is evidently curable, suggesting that the organisms were destroyed rather than made unrecognizable. In contrast, in neurosyphilis (a tertiary phase form) symptoms often persist after treatment, and I dont think anyone really knows whats happening. (If the disease could progress after treatment, I would conclude that the infection is not eradicated; but so far I havent heard that it does.)> =========================================== > Treponema Pallidum in early syphilitic lesions in humans during high-dosage Penicillin therapy, An Electron Microscopical Study> J. Wecke1, J. Bartunek2 and G. Stüttgen2, (1) -Koch-Institute, Berlin, Germany > (2) Department of Dermatology of the Free University of Berlin, Rudolf-Virchow-Hospital, Augustenburger Platz 1, D-1000 Berlin 65, Germany. Received: 8 September 1976 > > Summary The alterations of early syphilitic infection occuring in the course of high dosage penicillin (120 mega IU, 36 h) as clinical experimental trial has been studied both from the clinical and the electron microscopical views. By electron microscopical studies, findings revealing the localization and the status of treponemes before and during penicillin treatment could be established. Before treatment started, the majority of treponemes was of intercellular localization. In the course of treatment various forms of destruction could be differentiated. The most striking change in the host tissue after 7–8 h of penicillin therapy was an elimination of treponemes by penetrating phagocytes. 24 h after the beginning of treatment, treponemes could not be demonstrated any more. The clinical and serological findings after the high dosage penicilline will produce results comparabel to those of conventional therapie.

[Guest guest]

> Ok, am trying to understand. See if my logic holds : JHR is seen

with

> penicillin treatment of syphillis. In the case of this study, high-

dose

> pencillin rapidly rendered any treponemes undetectable. If we assume

> they were killed (which is likely in early stage infection, likely

> because we know that stage 1 is curable ?) and that the patients

> suffered JHR in this study (again likely ?),

I forget which phases JHR can occur in. But even if in the phase(s)

where it occurs, not all of them would have it, as it is a minority

experience according to some source that I vaguely remember. The

problem is I dont know what that sources standard is. Some of these

reactions are pretty much prostrating as I recall. Some sources

therefore might not count lesser, but still definite, effects as

being JHR. Its also possible that that source I'm remembering might

have been a low-quality source cited in anti-lyme polemic.

> then the JHR experienced

> would be due (at least in part) to the effects of the dead or dying

> treponemes. Would be more convincing with a few less assumptions...

>

> Seems like there may also be evidence of cytokine mediation. I

found a

> reference to a 1996 study, " Prevention of Jarisch–Herxheimer

> Reactions by Treatment with Antibodies against Tumor Necrosis

Factor

> [{alpha}] " , Fekade, M.D., Knox, M.B., Kebede Hussein,

M.B.,

> Amsel Melka, M.B., G. Lalloo, M.D., Ruth E. on,

F.I.M.L.S., and

> A. Warrell, D.M.

>

> The conclusion given in the abstract (don't have access to the full

> article) states that pretreatment with a sheep anti–TNF- [{alpha}]

> Fab suppresses the JH reaction in cases of louse-borne relapsing

fever

> (borrelia recurrentis) :

> http://content.nejm.org/cgi/content/full/335/5/311

> <http://content.nejm.org/cgi/content/full/335/5/311> .

>

> Do you have an opinion on this, ?

I see three possibilities that should be dealt with here. One is that

anti-TNF Fabs have some sort of non-TNF-mediated effect. This seems

mighty unlikely. But if you want to be really thorough you can

probably find experiments where normals or various sorts of patients

have been infected with Fabs with no relevant specificity (ie, that

wouldnt be expected to bind to anything).

Second, is that there is no change in TNF signaling during JHR (ie

TNF signaling is at baseline), yet the JHR phenomenon depends on TNF

not falling below baseline. Thus, the anti-TNF would ameliorate JHR

even tho JHR doesnt involve any changes in TNF signaling. Kind of

like, I guess, breathing doesnt make me type, but if I stopped

breathing I would stop typing.

Third possibility is of course that JHR is in fact mediated by

increased signaling by TNF (and probably other cytokines like IL-12,

IFNg, and IL-2).

Personally I'm well satisfied with the JHR/etc model in those

diseases. Since relapsing fever borreliosis and early syphilis

generally resolve under treatment as far as I know, going so far as

to not assume the organisms are killed is kind of just an alley to

glance down, to me. Even tho it doesnt lead to a dead end, I dont see

how it offers anything as sensible as what the classic understanding

offers.

Of course CFS is far far less understood.

[Guest guest]

Hi ,

By classic understanding, are you also including the cytokine production

(TNF, etc) or excluding that as a possibility ?

Thanks a bunch !

Carole

> Seems like there may also be evidence of cytokine mediation. I found

a reference to a 1996 study, " Prevention of Jarisch–Herxheimer

Reactions by Treatment with Antibodies against Tumor Necrosis Factor

{alpha}. Do you have an opinion on this, ?

> I see three possibilities that should be dealt with here. One is that

anti-TNF Fabs have some sort of non-TNF-mediated effect. This seems

mighty unlikely ... Second, is that there is no change in TNF signaling

during JHR (ie TNF signaling is at baseline), yet the JHR phenomenon

depends on TNF not falling below baseline. Thus, the anti-TNF would

ameliorate JHR even tho JHR doesnt involve any changes in TNF

signaling. ...Third possibility is of course that JHR is in fact

mediated by increased signaling by TNF (and probably other cytokines

like IL-12, IFNg, and IL-2).

> Personally I'm well satisfied with the JHR/etc model in those

diseases. Since relapsing fever borreliosis and early syphilis generally

resolve under treatment as far as I know, going so far as

to not assume the organisms are killed is kind of just an alley to

glance down, to me. Even tho it doesnt lead to a dead end, I dont see

how it offers anything as sensible as what the classic understanding

offers. Of course CFS is far far less understood.

[Guest guest]

> Hi ,

>

> By classic understanding, are you also including the cytokine

production

> (TNF, etc) or excluding that as a possibility ?

>

> Thanks a bunch !

> Carole

Yes, cytokine production would be included.

By the classic understanding of JHR signaling, I mean that conserved

bacterial molecule types (like bacterial liposaccharides and

lipoproteins) would be released in considerable amounts as bacteria

break down. These molecules bind to and activate human toll-like

receptors (TLRs), and TLR activation causes hefty cytokine release.

The above requires only the nonspecific arm of the immune system.

However when bacteria break down, they might /also/ release protein

antigens recognizable by the lymphocytes which control the specific

arm of immunity. This too might cause cytokine release. But I dont

think I have seen it considered much in what little formal work I

have read about the herx.

Either way (or both ways), the idea is the same: bacterial death

liberates bacterial molecules which are sensed by human cells,

causing them to release cytokines. Cytokines cause the symptoms of

immunoactivation (fever, hypotension, edema, agony, and death). Its

important to realize that TLR activators like " bacterial endotoxin "

(a common term for bacterial lipopolysaccharides and

lipooligosaccharides) are not directly " toxic " to human cells at the

relevant concentrations, as far as I know. Endotoxin does not impair

the function of any human system, as far as I know, except via

cytokines.