Immunophysiology and practical medicine (octt 13-short)

Natural Autoantibodies as Specific Immune Markers

of the Disease

Alexander PoletaevMedical Res. Ctr. «Immunculus»

P.K.Anokhin Res. Inst. of Normal Physiology

Moscow, Russia

2) Pre-disease correction

1) Pre-disease diagnostic

Crucial question (evaluation of effectiveness of the used medical paradigm):

Reparative Medicine

(The disease now presented should be

now treated)

Preventive Medicine(To reveal the pre-disease changes

– To prevent the disease)

In general ANY Medicine is imply prevention/ Just prevention of pre-term

death

If the biological limit of human life calculated nearly as 120-150 years - how many years (30? 50?) – an averaged person lose unjustified?

Individual genetic analysis do not have alternative for prediction of “monogenic diseases” (example: phenylketonuria). On the other hand the prediction of polyfactor diseases (most cancers, cardio-vascular diseases, etc.) are out of the field of responsibility of the molecular genetic

What can be proposed for early prediction of the most diseases?

Soon after the development of ELI-Test technology was

began (ELI-Test - from Enzyme-Linked Immuno-Tests)

ELI-Tests are based on analyses of the changes in profiles of the marker auto-Abs

ELI-Test methods were intend for a mass-scale prophylactic medical examination

Chernobyl Disaster (1986)

ELI-Test Technology:

It is based on ability of the Immune System to be natural “Magic Mirror” reflecting the health state of individual; including the beginning of any pathology (future disease) as well as the disease presented now

ELI-Test Technology was intended for:

a) Early revealing of any pathology at the beginning stages

b) Verification of the disease in not quite clear cases

c) Monitoring of the health state changes during the treatment course

ELI-Viscero-Test (24)

Marker sign of the Small Vessel’s

Vasculitis

Profiles of auto-Abs in

the blood serumNB: not the concentration!

Kidney insufficiencyHeart insufficiencyChronic obstructive lung diseaseTrophic ulcersStroke

Future problems

Case reportM.,42 y.o., no complains, clinically healthy

Habitual (bacteriologist’) views:

1) Predestination of the ISYS is the WAR and destruction

2) There are no place for Natural Autoimmunity in healthy organism!

Physiological view: Not War, but

Peace (homeostasis) is predestination

of the ISYSIts main functions are:

Autoidentification, Autoclearance, Autoreparation,

Ilya I.Mechnikoff(1845-1916)

Polly Matzinger (2002): Any tissue’s

injury accompanied by the transitory autoimmune reactions against tissue antigens.

It is physiological response to the damage. It provides:

a) Activation of the clearance (from dying cells and debris);

b) Activation of the tissue regenerative processes

The phenomenon of natural immune

autoclearance is the ground for ELI-Test

Diagnostic Technology

Principles of Autoclearance

Macrophages are blind for Self AG (absent receptors for self-AGs, but presented receptors (Fc-Rc) for AG-Abs complexes)

Antibodies play role of the pointing the finger (“signature”) for AGs whose should be “eaten” by macrophages

Fc-Rc

Macrophages + Auto-Abs (together) represents the Main Instrument of Autoclearance

Self-AG Ab

AG marked by Ab

> 100 milliards cells died in each healthy human daily (Silverman, 2011) This hazard “garbage” must be utilizingpermanently

ISYS is a house-keeper!

(neither a policeman nor KGB’s agent)

AUTOCLEARANCE has based on the phenomena of Natural Autoimmunity

Necessity in Autoclearance rise prominently if the pathology begins (in any organ and tissue)

Activation of Autoclearance = Activation of Sanogenic Autoimmunity

b) Motor or mental defects, or death

а) Complete rehabilitation

The transitory rise of “neurotropic” auto-Abs is a good prognostic sign

Absence of autoimmune reaction mean a bad prognosis

STROKE: If there is no activation of Auto-immunity after stroke – it means the clinical prognosis for the patient is rather bad (E.I.Gusev et al., 2004-2008)

Feed-back principle: (Experiments 1980-1985) Elevation of any of Self-AG (that is rise of its availability for the Immune System) lead to the rise of production of respective auto-Ab

“Conception of Immuno-Chemical Homeostasis of the Organism”

I.E. Kovalyov (1985)

Activation of the cell’s death (apoptosis)

Rise of expression or secretion of macromoleculesAdministration some AG in non-physiologic concentration

The Main Causes of AG elevation:

The phenomenon does not mean the autoimmune pathogenesis of the disease: It is a reflection of the compensatory elevated expression of (abnormally functioning) Ins-receptors

Pre-Diabetes: Rise of auto-Abs against insulin receptors as a marker of pre-diabetes and early stages of diabetes

type II Abs against Ins-Rc

Case report

“Autisic profiles” of the serum auto-Abs (ELI-Neuro-Test)

GFAP (~50% of cases)

Ach-R (~60% of cases)

5HT-R (~70% of cases)

Do the changes reflects abnormalities in expression of according receptors? Or what? (autoimmune

aggression?)

?

Besides elevated a-Abs against V-gated Ca-Ch, S100, DA-R (may be seen in ~20-

30% of cases)

-40,0

-20,0

0,0

20,0

40,0

60,0

ChGT

dsDN

A

b2-G

P

Collag

en

Rheu

mofac

tor

Insulin

Thyro

glob. S1

00

Spr06

TrM03

ANCA

KiM05

Анти-ХГЧ синдром

Example of iatrogenic disease: Iatrogenic Anti-Chorionic

Gonadotropin Syndrome in woman induced by the IVF procedure

(steady elevation of Ab against ChGT in more then 60% women after IVF with using of “Pregnyl” or “Choragon”)

Anamnesis Anti-ChGT Syndrome was diagnosed after preceded IVF (unsuccessful).

The Last Pregnancy:

• Placental malformation;

• Stillbirth at 22-24 weeks

Case report

ELI-Neuro-Test

ELI-ANCOR-Test

ELI-Pulmo-Test

ELI-Nephro-Test

ELI-SIC-Test

ELI-Repro-Tests

Adopted by The Ministry of

Health:

SIR SGLTPG

LGC

QVVKAE

GSCSPL

DNAIn

sulin

b2GPI

PPACPD

KEENFN

AGAADD

S100AFP

SPRColl

agen

AB_Glyc

erin

LLP_g

c

LLP

AB_new

NNS_PAA

NNS_gc

KLM_g

c

KLM Angios

tatin

-100

-50

0

50

100

150

200

250

300

Профиль аутоантител в сыворотке пациента (55Cr)

55_2

+2s

-2s

Auto-Ab profiles in patient with early stage of the breast cancer

Shading zone is equivalent

of “Two Sigmas”

(deviation from average normal

data)

ELI-Onco-Test dataCase report

Frequency of the organ pathology which has been (left bars) or not been (right bars) associated with the changes in serum contents of corresponding auto-Ab (General number of observations: n = 7308; p < 0.05 … p < 0.001)

From Dissertations:FEIGINA A.A. – Clinical and neuroimmune aspects of epilepsy after stroke. Moscow, 2008.LUCENKO Y.V. – Serum content of cardiospecific antibodies in children with heart arhitmias. Moscow, 2010.OSIPENKO Leeza – System dynamics in early health technology assessment: prenatal screening technology

(ELI-P Complex). Stevens Institute of Technology, Hoboken, NJ 07030, 2005.GENERALOVA G.A. – Renal autoantibodies in healthy state and during kidney’s pathology, Moscow, 2002.GNEDENKO B.B. – Immunochemical aspects of diabetic fetopathy. Moscow, 2001. KLUCHNIKOV S.O. – Ecological pathology in children. Complex investigations, Moscow, 1999.

Steady excess of anti-renal Abs and kidney's malfunction (p < 0.01)

0

100

200

(A) (B)

Steady rise of ANCA: corelation with vascular problems (p < 0.01)

0

50

100

150

200

(A) (B)

Excess of auto-Abs against GFAP (A) and seizure simptomes (p < 0.05)

0

5

10

15

20

25

30

35

40

(A) (B)

Auto-Immunity may be compared

with Double-faced Janus:

In the most cases it behaves like Good Dr. Jekill, but sometimes like Bad Mr.

Hyde

(Secondary) Primary injuries

lead to activation of specific adaptive autoimmune reactions (raising clearance and regeneration)

(Primary)

Activation of auto-immunity (not rela-ted to the needs of organism) leads to the pathology in the different organs

NATURAL AUTOIMMUNITY - PATHOGENIC AUTOIMMUNITY

Rose NR, Witebsky E - Thyroid autoantibodies in thyroid disease, Immunology, 1956; 76: 417-457

Auto-Ab as a markers of a disease (in future and now presented)

Ernst Witebsky Noel Rose

X-Ray, MRI, etc. provides the possibility to reveal the disease PRESENTED NOW

Infiltrative Tuberculosis of the left lobe of the lungs in stage of disintegration

It became possible to reveal

the disease even before its manifestation

• Do you wish to know?

• What should we to

do…?

Questions arise:

A man needs not only in a health. But he needs nothing if his health is poor

Socratus (469 – 399 B.C.)

Could the nutriciology, physiotherapy, homeopathy, acupuncture, etc. become an instruments for pre-disease health state correction?

(Lecture-2)

The Mother and the Child relations in the “Mirror of

AutoImmunity”

dsDNA

APS syndrome

ChGT

TrM-03

b2-GP I

Ig-Fc (RF)

S100

Insulin

Active intracellular infection

Zygote implantation and Placentation

Chronic inflammation

Abnormalities in apoptosis and Neural Tube

Collagen Scars/synechias forming

Platelets abnormalities

Vasculites and vasculopathiesАNCA

Diabetic fetopathy; Endothelial dysfunction

Thyroid pathology, Embriotoxic effects

Endometritis

Kidney pathology

Thyroglobulin

SPR-06

KiM-05

ELI-P-Complex (the first one elaborated after Chernobyl)

Profiles of auto-Abs in woman blood serumNB: not concen-tration

-40,0

-20,0

0,0

20,0

40,0

60,0

ChGT

dsDN

A

b2-G

P

Collag

en

Rheu

mofac

tor

Insulin

Thyro

glob. S1

00

Spr06

TrM03

ANCA

KiM05

Анти-ХГЧ синдром

Example iatrogenic disease: Iatrogenic Anti-Chorionic

Gonadotropin Syndrome in woman after IVF procedure

(steady elevation of Ab against ChGT in more then 60% women after IVF with using of “Pregnyl” or “Choragon”)

Anamnesis Anti-ChGT Syndrome was diagnosed after preceded IVF (unsuccessful).

The Last Pregnancy:

• Placental malformation;

• Stillbirth at 22-24 weeks

Case report

70,4%

29,6%

Anti-S100 Abs in HPV-infected women (E.N.Koshel et al., 2007-2010)

Elevated Abs against S100

Normal level of Abs against S100

(Vaccination against HPV in this context also may become problematic if lead to abnormal rise of Abs against S100)

10-12-times rise of the risk of neurology deviations

8-10-times rise of the risk of miscarriages and stillbirths

“Classic” investigation of a serum sample for auto-Abs to beta2-GPIdid not reveal any signs of APS because of individual immune supression

Investigation of the “profiles” of multiple auto-Abs permit to reveal a typical sign of APS (in spite of immune suppres-sion); red line above the patient data – upper limit of an averaged population immune reactivity

Case report

1-10

-8

-6

-4

-2

0

2

4

-7% from “population norm”

Satisfactory Results of a New Pregnancy in Women with a Habitual Miscarriages:

(A) Pre-gestational treatment was controlled by measuring of auto-Abs

(В) Without control of auto-Abs

0

10

20

30

40

50

60

70

80

A B

~ 70%

~ 12%

Six “storks” or one?!

Experimental modeling of Multiple Sclerosis:

1) In a normal state it is rather difficult to induce the disease by injections of MBP;

2) The disease can be easily induced if MBP injected upon inflammatory background

Immune activation is a factor of risk for post-vaccinal

complications

ELI-Vaccina-Test (are there Immune Deviations?)

-50,0

-30,0

-10,0

10,0

30,0

50,0

70,0

90,0

ds-DNA IF-g IF-a b2-GP Fc-Ig Coll

Used AGUsed AG (adsorbed in the wells)(adsorbed in the wells)

Results (profiles)Results (profiles) Normal rangesNormal ranges

dsDNAdsDNA --5500 -20…+10-20…+10

Interferon-gammaInterferon-gamma --4488 -20…+10-20…+10

Interferon-alphaInterferon-alpha +70+70 -20…+10-20…+10

betabeta2-2-Glycoprotein IGlycoprotein I --3232 -20…+10-20…+10

Fc-IgGFc-IgG ++9922 -20…+10-20…+10

Collagen IICollagen II --6644 -20…+10-20…+10

Case report

Maternal Immune Imprinting (a la Konrad

Lorenz) Transplacental transfer of maternal IgG Abs

Tuning of the lymphocytes of the fetus and newborn

Prominent similarity between the immune features of mother and her child (not father – child)

This phenomenon is the base for:

(а) Specific resistance to the infections before the direct contact with microbes;

(б) Sometimes it may be cause for the development of pathology of the same organ (heart, kidney, etc.) as it was in his mother

Maternal ELI-Viscero-Test data

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

-90

-80

-70

-60

-50

-40

-30

-20

-10

010

2030

4050

6070

8090

Норм

аПо

гран

ичны

е отк

лоне

ния

Дост

овер

ные о

ткло

нени

я

Ab to KiM-05 Ab to

Rc-TSH

Moderate proteinuria and decreasing of the blood TSH content was found in child (boy 2,5 y.o.)

Clinical case report: Woman, 36 y.o., Complains: fatigability, periodical elevation of blood pressure.

ELI-Viscero-Test data: 1) Signs of pathology in kidneys; 2) Signs of Thyroiditis

The Results of Additional Investigations: 1) Moderate bacteriuria and leucocytouria. Weak signs of pelvic inflammation; Spinal protrusions.

Diagnosis: Chronic pyelonephritis (subclinical); hypertension (early stage); Thyroiditis (early stage); Spinal protrusions

Case report

“Autisic profiles” of the serum auto-Abs (ELI-Neuro-Test)

GFAP (~50% of cases)

Ach-R (~60% of cases)

5HT-R (~70% of cases)

Besides elevated a-Abs against V-gated Ca-Ch, S100, DA-R (may be seen in ~20-

30% of cases)

Maternal Immune Imprinting can be the reason for the development of some forms of mental/neurology deviations in the children

?

GFAP

Emotional dysfunctions

NF-200

AChRc(n)

S100

MBP

GABA-Rc

DOPA-Rc

Gliosis (post-traumatic, post-ischemic)

Nervous fibers degenerative changes

Demyelinating diseases

Epilepsy, Psychoses

(V)Ca-chanel Myastenic syndromes

Myastenic syndromes

Epilepsy, Stroke Glu-Rc

Schizophrenia, Parkinson disease

Emotional dysfunctions, Bipolar disease

Opiate system dysfunctions

Opiate system dysfunctions

5HT-Rc

-Opiate Rc

Endorphine

ELI-Neuro-Test

73%

16%

11%

Child Health State (n = 589)

Healthy Children

Small deviations in a Health State

Poor Health State

17%43%

40%

45%

55%

Normal profiles of auto-Abs at pregnancy

The Health State of Child at age 3-4 years is directly related to the Immune State of Mother during her pregnancy

(Zamaleeva, Kluchnikov, 2002)

74 %

16 %

0 %

Moderate deviations in profiles of auto-Abs

Prominent deviations in profiles of auto-Abs

“The child’s health is

formed in the mother’s

Womb”

Professor Leonid

Persianinov:

Lets keep in mind Persianinov’s sentence