Repost of a talk by Klimas re immune dysfunction

[Guest guest]

I thought some of you would be interested in reading

an overview of Dr. Klimas' recent talk. Someone was

nice and wrote a summary. It includes a

brief explanation that may help in understanding how

the immune system is malfunctioning in our children,

how infections can become a factor, etc.

------------------------------------------------

by Rich V. Konynenburg

Klimas, M.D., is a Professor of Medicine,

Psychology,Microbiology and Immunology at the

University of Miami School of Medicine. She is the

Principal Investigator of one of the three NIH

sponsored CFS Research Centers. She has conducted

research on the immunology of CFS since the late

1980s. Her talk at the NIH CFS workshop on June 12,

2003, focused on the immune dysfunction observed in

CFS. She reported on a critical review of the

published papers in this field, presented what

appeared to her to be the consensus of this work,

discussed the problems with the existing data and the

difficulties in measuring immunological parameters,

and suggested guidelines for future efforts in this

field.

In summarizing the published work, the main

conclusions she presented were that there are a lot of

data indicating that there is chronic immune

activation in CFS, that there is a fair amount of

data demonstrating that there is a shift to a Th2 type

of immune response, there is considerable data showing

that there are changes in cytokine _expression, and

there are a lot of data showing lowered natural killer

cell activity (low NK cell cytotoxicity). In addition

she noted that there is evidence for elevated numbers

of immune complexes, elevated levels of antinuclear

antibodies (ANA),

higher prevalence of allergies, and an activated

Rnase-L pathway.

(Briefly, here's what these things mean: Chronic

immune activation means that the T lymphocytes, a type

of white blood cell that coordinates the activities of

the immune system, show evidence that

they have been alerted to the presence of a threat,

and they continue to remain in this alerted state,

whereas normally they would return to the inactivated

state after the threat was defeated. The shift to a

Th2 immune response means that instead of maintaining

a balance between a cell-mediated or Th1 type of

immune response and a humoral or Th2 type of response,

the immune system has shifted to a Th2 response and

stays " locked into " this type of

response. These two modes are both needed in order to

have protection against both normal bacteria, which

stay outside the human cells, and viruses and

intracellular bacteria, which enter human cells. Th1

operates by killing infected human cells. Th2

operates by making antibodies, which attach to normal

bacteria and other pathogens that are outside human

cells, so that they can be marked for killing by cells

specialized for this job. Both are

needed, but in CFS, the Th1 response is missing.

Cytokines are chemical messengers that are made by

white blood cells of various types to signal each

other, in order to coordinate the overall

immune response. They are also used to communicate

from the immune system to parts of the brain. For

example, some of them carry a signal to the

hypothalamus to produce a fever. Different patterns

of cytokine concentrations are found in the blood

during Th1 and Th2 immune responses, and this is one

way to identify the type of response that is dominant.

The natural killer cells are a type of

lymphocyte (a white blood cell) that is normally able

to kill infected cells without having to be cloned

specifically for a particular type of infection hence,

they are " natural " killers that are versatile enough

to kill any infected human cells that aren't

signaling that they are uninfected. Immune complexes

are combinations of antigens and antibodies to them

that are joined together in a " clump. " An antigen is

usually a protein that is part of a virus or a

bacteria, or something else that's " foreign. " An

antibody (also called an immunoglobulin) is a protein

that is made to recognize a specific antigen and bind

to it. Antinuclear antibodies are antibodies against

the nuclei of human cells. Allergies are cases in

which the immune system unfortunately responds against

something that is not actually a threat. The RNase-L

pathway is a pathway in all cells that can be

activated by viral infections or toxins and that

results in destruction of messenger RNA, both that

produced by viruses and that produced by the human

cells themselves. Activation of this pathway is sort

of a desperate move on the part of the cell to prevent

the proliferation of viruses, while at the same time

interfering with the ability of the

cell to make its own proteins. It is analogous to an

army firing artillery at its own soldiers' positions

(hopefully they are in foxholes) in order to kill an

enemy force that has overrun their positions.)

also noted that there is a correlation between

immune parameters and symptoms. In particular, when

low NK cell activity and elevated T-cell activation

are combined together, they are found to correlate

well with increased symptom severity. Patients with

high cognitive difficulty are found to have high

neopterin levels (Neopterin is produced by activated

macrophages. A macrophage ( " big swallower " ) is a type

of cell that is able to engulf and digest

another cell.)

also briefly mentioned the experiment in which

her group removed lymphocytes from lymph nodes of

PWCs, placed them in a culture designed to shift them

to a Th1 type of immune response, and reinjected them

into patients, successfully shifting the immune

response temporarily away from Th2 in seven patients.

Six of them exhibited significant improvement in

cognitive function and fatigue

for a while.

She also mentioned her group's work on PWCs who

underwent the stress of Hurricane . This turned

out to produce chronic stress for

many people, because of severe damage to their houses

(she mentioned roofs being blown off). They found

that the PWCs who had lower cognitive difficulty also

tended to have better immune function.

Those with lower NK cell function also tended to have

more severe fatigue and worse cognitive function.

also noted that her group has done some work to

try to develop an understanding of the mechanism of

the immune dysfunction. In particular, they have

found that the NK cells in PWCs are low in

perforin, which is the substance they normally use to

punch holes in infected cells in order to inject

granzymes to kill them.

Among the problems she mentioned with the existing

data were that the populations studied were

heterogeneous, were not well described,

and were frequently too small for statistical

significance to be achieved; the studies were

performed over a period of about 15 years

during which time the case definition for CFS changed;

methodology was not standardized so that it is

difficult to make comparisons between studies; the

immune parameters change over the course of time

because of remission relapse cycles, the monthly

hormonal cycle in women, and the circadian rhythm,

none of which were accounted for; and sufficient

attention was not paid to the fact that

immunological samples " do not travel well " and that

the laboratories doing the analysis of samples must

" know what they are doing. " For the future, she

recommended longitudinal studies rather than cross

sectional studies as were done in the past, and

efforts to avoid these other problems noted in the

past studies.

SNIP>>>

__________________________________________________

[Guest guest]

Hi, .

I'm the " someone. " I'm glad you found the summary useful! (:-)

Rich

--- In , <thecolemans4@...>

wrote:

>

> I thought some of you would be interested in reading

> an overview of Dr. Klimas' recent talk. Someone was

> nice and wrote a summary. It includes a

> brief explanation that may help in understanding how

> the immune system is malfunctioning in our children,

> how infections can become a factor, etc.

>

> ------------------------------------------------

>

>

> by Rich V. Konynenburg

>

> Klimas, M.D., is a Professor of Medicine,

> Psychology,Microbiology and Immunology at the

> University of Miami School of Medicine. She is the

> Principal Investigator of one of the three NIH

> sponsored CFS Research Centers. She has conducted

> research on the immunology of CFS since the late

> 1980s. Her talk at the NIH CFS workshop on June 12,

> 2003, focused on the immune dysfunction observed in

> CFS. She reported on a critical review of the

> published papers in this field, presented what

> appeared to her to be the consensus of this work,

> discussed the problems with the existing data and the

> difficulties in measuring immunological parameters,

> and suggested guidelines for future efforts in this

> field.

>

> In summarizing the published work, the main

> conclusions she presented were that there are a lot of

> data indicating that there is chronic immune

> activation in CFS, that there is a fair amount of

> data demonstrating that there is a shift to a Th2 type

> of immune response, there is considerable data showing

> that there are changes in cytokine _expression, and

> there are a lot of data showing lowered natural killer

> cell activity (low NK cell cytotoxicity). In addition

> she noted that there is evidence for elevated numbers

> of immune complexes, elevated levels of antinuclear

> antibodies (ANA),

> higher prevalence of allergies, and an activated

> Rnase-L pathway.

>

> (Briefly, here's what these things mean: Chronic

> immune activation means that the T lymphocytes, a type

> of white blood cell that coordinates the activities of

> the immune system, show evidence that

> they have been alerted to the presence of a threat,

> and they continue to remain in this alerted state,

> whereas normally they would return to the inactivated

> state after the threat was defeated. The shift to a

> Th2 immune response means that instead of maintaining

> a balance between a cell-mediated or Th1 type of

> immune response and a humoral or Th2 type of response,

> the immune system has shifted to a Th2 response and

> stays " locked into " this type of

> response. These two modes are both needed in order to

> have protection against both normal bacteria, which

> stay outside the human cells, and viruses and

> intracellular bacteria, which enter human cells. Th1

> operates by killing infected human cells. Th2

> operates by making antibodies, which attach to normal

> bacteria and other pathogens that are outside human

> cells, so that they can be marked for killing by cells

> specialized for this job. Both are

> needed, but in CFS, the Th1 response is missing.

> Cytokines are chemical messengers that are made by

> white blood cells of various types to signal each

> other, in order to coordinate the overall

> immune response. They are also used to communicate

> from the immune system to parts of the brain. For

> example, some of them carry a signal to the

> hypothalamus to produce a fever. Different patterns

> of cytokine concentrations are found in the blood

> during Th1 and Th2 immune responses, and this is one

> way to identify the type of response that is dominant.

> The natural killer cells are a type of

> lymphocyte (a white blood cell) that is normally able

> to kill infected cells without having to be cloned

> specifically for a particular type of infection hence,

> they are " natural " killers that are versatile enough

> to kill any infected human cells that aren't

> signaling that they are uninfected. Immune complexes

> are combinations of antigens and antibodies to them

> that are joined together in a " clump. " An antigen is

> usually a protein that is part of a virus or a

> bacteria, or something else that's " foreign. " An

> antibody (also called an immunoglobulin) is a protein

> that is made to recognize a specific antigen and bind

> to it. Antinuclear antibodies are antibodies against

> the nuclei of human cells. Allergies are cases in

> which the immune system unfortunately responds against

> something that is not actually a threat. The RNase-L

> pathway is a pathway in all cells that can be

> activated by viral infections or toxins and that

> results in destruction of messenger RNA, both that

> produced by viruses and that produced by the human

> cells themselves. Activation of this pathway is sort

> of a desperate move on the part of the cell to prevent

> the proliferation of viruses, while at the same time

> interfering with the ability of the

> cell to make its own proteins. It is analogous to an

> army firing artillery at its own soldiers' positions

> (hopefully they are in foxholes) in order to kill an

> enemy force that has overrun their positions.)

>

> also noted that there is a correlation between

> immune parameters and symptoms. In particular, when

> low NK cell activity and elevated T-cell activation

> are combined together, they are found to correlate

> well with increased symptom severity. Patients with

> high cognitive difficulty are found to have high

> neopterin levels (Neopterin is produced by activated

> macrophages. A macrophage ( " big swallower " ) is a type

> of cell that is able to engulf and digest

> another cell.)

>

> also briefly mentioned the experiment in which

> her group removed lymphocytes from lymph nodes of

> PWCs, placed them in a culture designed to shift them

> to a Th1 type of immune response, and reinjected them

> into patients, successfully shifting the immune

> response temporarily away from Th2 in seven patients.

> Six of them exhibited significant improvement in

> cognitive function and fatigue

> for a while.

>

> She also mentioned her group's work on PWCs who

> underwent the stress of Hurricane . This turned

> out to produce chronic stress for

> many people, because of severe damage to their houses

> (she mentioned roofs being blown off). They found

> that the PWCs who had lower cognitive difficulty also

> tended to have better immune function.

> Those with lower NK cell function also tended to have

> more severe fatigue and worse cognitive function.

>

> also noted that her group has done some work to

> try to develop an understanding of the mechanism of

> the immune dysfunction. In particular, they have

> found that the NK cells in PWCs are low in

> perforin, which is the substance they normally use to

> punch holes in infected cells in order to inject

> granzymes to kill them.

>

> Among the problems she mentioned with the existing

> data were that the populations studied were

> heterogeneous, were not well described,

> and were frequently too small for statistical

> significance to be achieved; the studies were

> performed over a period of about 15 years

> during which time the case definition for CFS changed;

> methodology was not standardized so that it is

> difficult to make comparisons between studies; the

> immune parameters change over the course of time

> because of remission relapse cycles, the monthly

> hormonal cycle in women, and the circadian rhythm,

> none of which were accounted for; and sufficient

> attention was not paid to the fact that

> immunological samples " do not travel well " and that

> the laboratories doing the analysis of samples must

> " know what they are doing. " For the future, she

> recommended longitudinal studies rather than cross

> sectional studies as were done in the past, and

> efforts to avoid these other problems noted in the

> past studies.

> SNIP>>>

>

>

> __________________________________________________

>

[Guest guest]

Thank you, Rich! It was one of the most helpful

posts, and I've referred back to it so many times in

trying to comprehend this!

But it was Cheryl who had posted that original comment

- I need to make sure I identify when I'm not the one

with the summary. She is the brilliant mind that

could summarize the importance of the posts and

abstracts and I'll try to make note when the comments

were someone elses. (Forgive me if I get in a hurry

and forget!)

--- rvankonynen <richvank@...> wrote:

> Hi, .

>

> I'm the " someone. " I'm glad you found the summary

> useful! (:-)

>

> Rich

>

>

>

> >

> > I thought some of you would be interested in

> reading

> > an overview of Dr. Klimas' recent talk. Someone

> was

> > nice and wrote a summary. It includes a

> > brief explanation that may help in understanding

> how

> > the immune system is malfunctioning in our

> children,

> > how infections can become a factor, etc.

>

__________________________________________________

[Guest guest]

Thanks Rich for that overview. I haven't seen anything define the terms and

put it all together so concisely before. I sent it along to family so that

they will have a better understanding of what my kiddo is fighting against.

April

[Guest guest]

Hi, April.

I'm glad you found my review of Klimas's talk helpful. I don't

know if you received all of it, since part of it appears to have been

chopped off on the version posted to this list. The full review,

including my interpretation of the immunological observations in CFS

can be found at the following website:

http://www.immunesupport.com/Library/showarticle.cfm/ID/4912/HealthWatc

h/HealthWatch-Treatment-Guide-2003

Rich

>

> Thanks Rich for that overview. I haven't seen anything define the

terms and

> put it all together so concisely before. I sent it along to family

so that

> they will have a better understanding of what my kiddo is fighting

against.

>

> April

>

[Guest guest]

Hi, .

Thanks to both of you!

Rich

> > >

> > > I thought some of you would be interested in

> > reading

> > > an overview of Dr. Klimas' recent talk. Someone

> > was

> > > nice and wrote a summary. It includes a

> > > brief explanation that may help in understanding

> > how

> > > the immune system is malfunctioning in our

> > children,

> > > how infections can become a factor, etc.

> >

>

> __________________________________________________

>