AUTOIMMUNE DISORDERS (ORGAN SPECIFIC & SYSTEM SPECIFIC)

Autoimmunity, Definitions
Disorder, disease, syndrome
History & tolerance
Mechanism of Autoimmunity
Graves disease
Hashimotos disease
Type 1 diabetes
Myasthenia gravis
Multiple sclerosis
Autoimmune encephalomyelitis
Good pasteur syndrome
Autoimmune haemolytic anaemia
Addisons disease
Rheumatoid arthritis
Systemic lupus erythematosis
Psoriasis, scleroderma
Immune thrombocytopenia
Inflammatory bowel disease
Guillain barre syndrome
Sjogren Syndrome & celiac disease
Wegeners granulomatosis
Treatment and prevention

1. BHARATHIAR UNIVERSITY
DEPARTMENT OF MICROBIAL BIOTECHNOL
IMMUNOLOGY AND IMMUNOTECHNIQUES

AUTOIMMUNE

presented By

Dr. K. PREETHI SABARIDARAN.B
Assistant Professor I M.Sc. Microbiology

2. \ nd
CONTENTS

Introduction

Definitions

History

Tolerance

Mechanism of autoimmunity

Organ specific autoimmune diseases
System specific autoimmune disease
Treatment

Prevention

3. + Autoimmune disease are conditions in
which your immune system mistakenly
damages health cells of your body

+ Usually your immune system can tell the
difference between forgein & body cells.

+ Butif you have autoimmune diseases
immune system mistakenly release
proteins called “autoantibodies " that
attack healthy cells

+ Doctors identified more than 100
autoimmune diseases which affects 24
million people

+ Its not clear that what causes or triggers
them, app 40% human disease are
autoimmune.

4. DEFINITIONS

DISEASE:

Resulting from pathophysiological response to
external or internal factors, they cause both physical À
and emotional signs

Eg: Cardiovascular disease

DISORDER:

Adisruption of the disease to the normal or regular
functions in the body or a part of the body
Eg: Cardiovascular disease to arrhythmia ‘

5. SYNDROME:

The terms that refers to a disease or a disorder that
has more than one identifying feature or symptom
(or) a collection or set of signs & symptoms that
characterise particular disease
Eg: HIV- AIDS

CONDITION:

Sometimes a syndrome caused by number of
diseases it can be medical condition. An abnormal
state of health that interferes with usual activiti

ities.
Eg: Chronic fatigue Syndrome

6. HISTORY

Serge Metalnikoff (1900) reported some animals for
antibodies against own spermatozoa

Paul Ehrlich (1901) rejected concept that organisms immune
system could attack own tissues "horror autotoxin"

Julius Donath & Karl Landsteiner (1904) reported autoantibodies
cause disease by showing hemolysin which cause paroxysmal
cold

Ernst Witebsky and Noel Rose (1956) were able to induce
experimental autoimmune thyroditis mediated by

autoantibodies KEN de
~ i”

7. Normal immune system must differentiate between
self & non self. Immunological tolerance
unresponsiveness to an antigen that is induced by
exposure of specific lymphocytes to that antigens

FAILURE OF SELF TOLERANCE:
Lack of responsiveness to individual own antigen.
Underlies our ability to live in harmony with our

cells and tissues. Autoimmunity results the loss * O +
of self tolerance sig

TYPES OF TOLERANCE: ©

1. Central tolerance 1,8 ©
2. Peripheral tolerance $

9. MECHANISM OF AUTOIMMUNITY

Y AG RELEASED FROM HIDDEN LOCATION : |S « Y
a :
Many self Ag found in hidden location eg: CNS, Testes, Eye = SQ
stimulate Autoimmunity 3

SU
NN

Organ damage -> Hidden Ag released -> Reaches blood stream ->. (a N\
Encounter Ag sensitive cells -> Stimulate autoimmunity .

AG GENERATED BY MOLECULAR CHANGES

Development of completely new epitopes on normal protein eg:
RF immuno conglutinine

Ab + Ag -> new epitopes exposed on Fc region of Ab -> Stimulat
formation of RF -> Establishment of disease like RA, SLE

10. MOLECULAR MIMICRY

Sharing of epitopes between an infectious agent & its host. Ab
directed against agents starts reacting with normal self Ab.
Triggers autoimmunity

Y ALTERING IN AG PROCESSING

AT cells may fail to develop tolerance to an self Ag simply because it is
not efficiently procured. If something happens to improve processing
an autoimmune disease may triggered. This is usually happens at site of
inflammation that resulting in modified Ab. Eg: Diabetes

Y INFECTION

Here autoimmunity is not due to infectious agent itself, but

results from regulation of immune response by microbes. 4

a

11. Y GENETIC FACTORS = ee,

There is increased expression of Class 2 HLA antigens on tissues
involvedfin autoimmunity. Increased familiafincidence, high in
twinf(mondzygotic>dizygotic) favouring bias most

N
associated with multiple genes >
/ » à.
ENVIRONMENTAL FACTORS
UV Fay kause cell déath, leads response to lupus, Smoking the risk
factor for RA, chemical modified self antigen, doth genetic bias,

more common in women> men, hormones and Tr mechanism.

\ ap A LL
LYMPHO! ES ABI MALITIES y 3: *

Primary abnormalities ither B cell or Tc ince they are critical
regulators. Abnorm: ities in lymphocytes could affect any one of [D
the mechanismithat normally maintains self tolerance na

a

12. @ FAILURE OF CENTRAL TOLERANCE , ©

Inside the primary & secondary lymphoid organs, positive, negative selection

(Deletion of self reacting T cells in thymus apoptosis) failure of tolerance Sige
x -
@ PERIPHERAL TOLERANCE (ANERGY) SS 7 ec

T and B cells require more than just ligation of the antigen specific receptor. In
absence of co stimulatory signals cells enter state of anergy. The cells in Anergy are
unable to fully respond to normal Ag

Y POLYCLONAL LYMPHOCYTE ACTIVATION

Stimulation of non deleted self reacting lym ph ocytes. These are activated by some
activators LPS polyclonal B cell activators, Bacterial super Ag polyclonal T cell
activators

S Other causes include Sex, Family history, Environment, Nutrition, Q \
À

Health condition, Ethnicity ON

13. Organ Specific
Autoimmune Diseases |

Grave's Disease

Hashimoto's Disease

Type 1 Diabetes

Myasthenia Gravis

Multiple Sclerosis

Autoimmune Encephalomyelitis
Good Pasture Syndrome
Autoimmune Haemolytic Anaemia
Pernicious Anaemia

Addison's Disease

14. Organ specific autoimmune diseases is one in which
an immune response is directed towards antigens in a
single organ or a gland.

Lymphocytes or antibodies bind to cell membrane
antigens causes cellular lysis and inflammatory
response. Gradually damaged cellular structure is |
replaced by connective tissue (fibrosis). Function of |

organ declines ¿a rs,
a - = - = =

15. \ 2 4

The condition that leads to an N
overactive thyroid gland
(hyperthyroidism), when body
makes too much of hormones NY
(thyroxine & triiodothyronine) the
condition called hyperthyroidism. It

is common in women over age 20

GRAVE'S DISEASE.

GRAVES EYE DISEASE SYMPTOMS

GRAVES' OPHTHALMOPATHY OR GRAVES’ ORBITOPATHY (GO)

+ Dry gritty, and imitated eyes
+ Trouble moving the eyes
+ Vision loss

+ In graves disease so
also goiter

Symptoms: Anxiety, breast enlargement in men, irregular mensural periods, Rapid heartbeat,
eyeballs bulging out & painful, irritated eye, itchy, double vision, damage to cornea

Diagnosis: Increased heart rate, enlarged thyroid, Blood test - TSH, T3, T4, Scan, Orbit scan

Ga. am

16. Chronic thyroiditis or hypothyroidism caused by
| reaction of immune system against thyroid gland. The
| thyroid hormone level become lower than normal

" Antibodies against thymoglobulin -> Thyroid epithelial
cell -> Complement mediated lysis -> organ inflamed ->

QA GOITER
Hashimoto's Disease

Symptoms: Constipation, Fatigue, Hair loss, dry skin,
intolerance to cold, shrunken thyroid gland

Normal thyroid
‘larynx (voice box Diagnosis: Free T4 test, Serum TSH, T3, thyroid
_ Enlarged thyroid wp autoantibodies, CBC, serum prolactin, sodium,

(hey
KE)
oy 5 ¢ total cholestrol
“Trach ,
CD QU MA

17. TYPE 1
DIABETES

Type 1 diabetes lifelong (chronic)
disease which there is a high level of
sugar (glucose) in blood. Loss of self
tolerance associated with MHC
changes made in HLA DR4 loci on
chromosome 6

Symptoms: High blood sugar, thirsty, hungry,
AOD tired, blurry eyes, rapid breath,

DD

Insulin-

18. Symptoms: Low blood sugar, headache,

JD hunger, shaking, nervousness,
irritability, sweating, weakness,
hypoglycemia

Diagnosis: Fasting blood glucose level,

Random (non fasting), oral
glucose tolerance test,
Hemoglobin AIC

+

REGULAR
HEALTH
SCREENINGS

is; HLA -oR, loci —

á y
Matan enset Juvesthe
dfabetes
y al
Dali Olurose Transport Acie ar o
Tas acceptors on e) bts 4 Langarhatı
Be Complement medtated
re \rwulin receptor Binds Y Date
uth aber las >
> Pestrutièn Cells
mo tall trarpet Le
Dfabetes a

No Troulth produced

19. A neuromuscular disorder, involves muscle and nerve
control. The antibodies that block muscle cells from
receiving messages (neurotransmission) from nerve
cells. Some were linked to tumors

Symptoms:

Weakness of voluntary muscles, double vision,
drooping eyelids, breathing, talking & swallowing
difficulty, choking, drooping head, faccid paralysis,
fatigue, hoarseness or change in voice

Diagnosi
Blood test to check acetylcholine receptor, CT, MRI scan,
nerve conduction study, EMG, pulmonary function test

20. MULTIPLE
SCLEROSIS

Multiple sclerosis that affect brain and spinal cord (CNS), affect women
more. They cause by damage to myelin sheath.

The protective covering that surrounds nerve cells. When this nerve
covering is damaged nerve signals slow or stop.

Nerve damage caused by inflammation that occur area of brain, optic

Loss of balance, muscle spams, numbness, walking problem,
tremor, weakness, constipation, difficulty to urinate, double

vision, vision loss, facial pain, depression, dizziness, hearing {
loss, problem with erection, vaginal lubrication

nerve, spinal cord.

Symptoms:

21. Diagno:

Nerve reflex, eye examination, MRI, Brain scan, blood
test, lumbar puncture of CSF, spine, nerve function

me,

5 Br Aube ns

a

palas

u Neurm 1e denuzeltnated
Seche plage
ms
Ea
So Conuctién © no Combuali of nl

Multiple sclerosis

Central: —
- Fatigue

impairment = Optic neur
-Depression - Diplopia
pwd Speech:

- Unstable mood “Dysarthria

Throat:
- Dysphagia
Musculoskeletal:
- Weakness
- Spasms
- Ataxia
Sensation:
- Pain
- Hypoesthesias
- Paraesthesias
Bowel:
- Incontinence
- Diarrhea or
constipation

Jrinary:-

- Incontinence

- Frequency or
retention

22. AUTOIMMUNE
ENCEPHALOMYLETITIS

Autoimmune encephalitis one of most
common cause of non infectious encephalitis
triggered by tumors, infection or cryptogenic
response against neuronal autoantigens with
production of antibodies

Symptoms:

Ataxia, dystonia, sweating, hypertension,

hypoventilation, insomnia

Diagnosis:

CSF pleocytosis, MRI, EEG, blood serum, IgG Mn ©
4

index, Brain biopsy
Ll AP >

23. Ÿ 4 ZF Goodpasture Syndrome

Anti-Glomerular Basement Membrane Disease

GOOD PASTURE
SYNDROME

Immunesystem makes antibodies to
fight off germs, but with syndrome it
attacks lungs & kidney. It leads
inflammation of kidney
(glomerulonephritis) and failure. It can
be fatal it not quickly diagnosed and
treated.

Symptoms:

Kidneys

Nausea, pale skin, coughing up blood, small amounts of blood in urine (hematuria),

protein in urine (proteinuria) E

fi . £ )
Diagnosis: -
Blood test to detect Abs, urine test (WBC, cellular material),
kidney biopsy, chest X ray

Lungs

24. AUTOIMMUNE HAEMOLYTIC
ANAEMIA ey

\ Ä
| Symptoms:
AIHA characterised by formation of Fever, shortness of breath, jaundice,
autoantibodies against patients own red cells. muscle pain, dark pee, heart palpitations,
Depending upon: diarrhea, dizziness, arrhythmia

Warm antibody AIHA: antibodies are reactive at Diagnosis:

body temperature 37°C they generally coated by CBC, size of RBC, hemoglobulin content,

IgG class antibodies and occasionally IgA hematocrit, peripher: ilirubin
test, coombs test, r nt

Cold antibody AIHA: autoantibodies Hemolytic Anemia
react better with 4°C IgM binds,
aggulutation form

25. PERNICIOUS au
ANAEMIA

The condition which body does not have Pornicious anseula

enough healthy RBC provided O2 to body “méme sain stomach cts
tissues. The condition occurs when the pend es eee
intestine cannot absorb Vit B12. Special 5 Did cats
.

protein called intrinsic factor IF binds vit B12 E Anemic process
that absorbed in intestine, when stomach
does not make IF intestine will not absorb.

IF and B12
bing together

Symptoms:
Diarrhea, nausea, fatigue, pale skin, heartburn:
swollen red tongue, bleeding gums, irritability,
optic nerve atrophy, hallucinations

Stomach
Diagnosis:

aR E Small
3 intestino
CBC, LDH, serum bilirubin, reticulocyte level, 212 | 1
2°
B12 deficient blood

Vitamin B12 level, homocysteine level in blood 812 cannot |

‘enter blood stream

26. DISEASE The disorder that cause the adrenal gland to not
produce enough hormones. They produce
° lucocorticoid, mineralocorticoid, sex hormones. The
ADDISON'S DISEASE 9
disease results damage of Adrenal cortex

caycemia Symptoms:

DAN

Abdominal pain, dehydration, skin darkening, low y

grade fever, weight loss, fatigue, loss of appetite
, Diagnosi:

Blood test, increases K+, low cortisol level, low Na2+,
low pH, increased eosinophil count, abdominal pain, X
ray, CT scan, co syntrophin (ACTH) stimulation test

27. System Specific

Autoimmune Diseases

Rheumatoid Arthritis
Systemic Lupus Erythematosis
Celiac Disease

Sjôgren Syndrome
Inflammatory Bowel Disease
Psoriasis

Autoimmune Vasculitis
Scleroderma

Guillain Barré Syndrome
Wegener's Granulomatosis
Immune Thrombocytopenia

28. RHEUMATOID
ARTHRITIS ¿

RA is a disease that leads to inflammation of the deformity
tae A n ; of thumb
joints & surrounding tissues. It is a long term
disease also affect other organs. Cause is not

: : Jinar deviation of ——
known, the immune system of body mistakenly netacarpophalangeal
attacks health tissues. Le

«neumatoid arthritis
(late stage)

4

‘Swan-neck deformity

Progressive debilitating inflammatory disease of
connective tissue, common site joints affects
frequently at movable joints, hands and feet

Healthy joint

J Symptoms:
7 Minor joint pain, stiffness, fatigue, morning stiffness, joints feel
\ warm, tender, swollen joints, chest pain (pleuristy), dry eye,

\ Pannus formation, nodules under skin

29. Diagnosis:

Rheumatoid factor, Anti CCp Ab,
CBC, metabolic panel, uric acid,
C reactive protein, ESR, joint x
ray, ultrasound, MRI, joint fluid
analysis

¿| Zemmanı complex. form jet cartty

4
Attendu Complemento
Geren | cum
Stma \
yde responce
Soul nl, Rad »
NE ee ied

para Bate ef Diefüetten

30. tc)
sus

SYSTEMIC LUPUS

ERYTHEMATOSIS IR
An autoimmune disease that affect skin,
joints, kidney, brain and other organs
hence a multisystem autoimmune

disease. Immunologically the disease is 5
associated with enormous array of
autoantibodies classically including ¡A

antinuclear antibody

Symptoms: Chest pain, hair loss, mouth sore, discomfort malaise, fever, fatigue, skin rash,
swollen lymph node, (butterfly rash),

f 3) Brain - headaches, memory and vision loss, Heart - inflammation

Lungs - build in pleural space, bloody cough, Skin - sore in mouth
y Y Kidney - leg swell, Blood - anemia, decreased platelets & WBC 30

31. Diagnosi

Antinuclear antibody, CBC, Urinanalysis, wer

serum creatinine, complement

components, coombs test, ESR, CRP, EEE € eal a
battues

kidney and liver function test, RF, biopsy, Basal Aare

Imaging organs
Inflammatory IN i
Vai response To
„an Tu AS
[Cert (AOS
ión b ey pay
Le appel Lupus - De. Lali
Larine - Skin

Lonnective issue.
Aoc - Antibody perdent Cellular Gplötortettz.

)

R92 és

ee ee

32. Celiac Disease

Lining of small intestine

CELIAC
DISEASE

Gluten sensitive enteropathy that damage lining of small
intestine, it comes from eating gluten substance found in
wheat, rye, barley, oats. It damage intestine and not able to
absorb nutrients. When people with celiac disease eat gluten ©
foods, immune system reacts by damaging villi, because of
damage villi unable to absorb iron, vitamins and nutrients
Symptoms: Ñ
& Large intestine
Abdominal pain, constipation, decreased appetite, Diarrhea, lactose intolerance, nausea,
vomiting, weight loss, stool with foul smell a
Diagnosis:
Bone density, cholesterol, CBC, serum folate & iro!
vit B12 level serum, vit D level, ferritin level,
comprehensive metabolic panel

Damaged villi (celiac) Normal vill

| ~ Stomach

Small intestine

evel, prothrombin time,

33. . a sd a y
SJOGREN

SYNDROME © &

The syndrome in which the glands that produce
tears and saliva are destroyed. This cause dry mouth?
& eyes. It affect other parts like kidneys & lungs. It
may occured by other clinical conditions also

Symptoms:

A 4 ds R A outh increase tooth decay
Itching eye, burning sensation in eyes, difficulty in = 2

swallowing & eating dry food, loss of taste, hoarseness, teeth decay,
gum inflammation, sores and pain in mouth, fever, skin rash
Diagnosis: >
CB chemistry, liver enzymes, Urinanalysis, RF, cryoglobulins, protein
electrophoresis, schirmer test, salivary gland biopsy, MRI of salivary
gland, chest X ray, skin biopsy

34. Ulcerative
colitis

{Colon walt

INFLAMMATORY >). (+
BOWEL DISEASE -

IBD a group of disorder that cause Chronic inflammatio!
(pain & swelling) in intestine

CROHN'S DISEASE: cause pain and swelling in the digestive
tract. It can affect any part from the mouth to anus. It most
affect small intestine & upper part of large intestine. x
ULCERATIVE COLITIS: cause swelling and sore (ulcers)
intestine, colon and rectum in

Urcoratve
surco

Continuous
inflammation

Thickening
‘of colon wall

ww
Symptoms:
Abdominal pain (belly), diarrhea, constipation, bowel urgericy, gas and bloating, unexplaine
weightloss, loss of appetite, mucus or bloody stool, upset stomach, fever, sore ulcers
Diagnosis: O
CBC, colonoscopy, EUS endoscopic ultrasound, flexible,

35. Psoriasis an autoimmune chronic skin condition
characterized by inflamed red, raised areas, often an
developed into silvery scales on scalp, elbows, knees, Psoriasis

lower back. It can associated with arthritis An Autoimmune Disease

Symptoms: Diagnosis:
Examination of skin and nails for
development of silvery scales,

skin biopsy —— a.

35

Plaque psoriasis - patched red, raised skin on
trunk, arm, legs, knees, elbow, scalp
Gut rates psoriasis - spot of red, skin,

pustular psoriasis - small pustules (blisters) VON

36. AUTOIMMUNE® $
VASCULITIS ¿>

The disease that cause inflammation in your blood
vessels. The swelling makes it hard for blood to flow
through your affected vessels which can cause organ
and tissue damage. The swelling of blood vessels
(arteries, veins, capillaries)

Symptoms:
Trouble in breathing, coughing, rashes, fatigue,
joint pain, strokes
Diagnosis:

functions of affected organs

37. SCLERODERM

‘Scleroderma

Thick, wany skin

Also called systemic sclerosis tht affect your skin,
connective tissue & internal organs. It happens
when your immune system cause your body to
make too much of protein collagen an important
part of your skin as result skin get thick, tight, scar
forms in lungs and Kidney

Symptoms:

Hardening & thickening skin, ulcers or sores on your fingertips,
small red spots on face and chest, swollen joint, edema,
heartburn, diarrhea, from oval shaped patches on skin

Diagnosis: zug EE

Physical examination, X ray, CT, blood test, Gl test, ¡Aa
lung function test, heart test EKG and ECG, biopsy

38. Guillain-Barré syndrome (GBS) re _

Neuron (nerve cell)

GUILLAIN BA
SYNDROME =

GBS is problem with your nervous system. It
cause muscle weakness, reflex loss, numbness,

tingling in parts of your body which leads nt iii
Paralysis. It can cause, affect to anyone but out mazea ea
most common people above 50 years old.

Symptoms:

Pin & needle sensation in fingers, toes, ankles or wrist, weakness

in legs, unsteady walking, difficulty in facial movements, \

speaking, chewing, swallowing, double vision, difficulty in
bladder control or bowel function, rapid heart rate
Diagnosis:

Neurological examination, tendon reflex, lumbar
puncture, EMG, blood test, nerve condition studies

39. MATOSIS GPA Granulomatosis with polyangiitis also

called (WG) WEGENER'S GRANULOMATOSIS,

inflammation of blood vessels in your nose,
sinus, throat, lungs & kidney

Symptoms:
Pus like drainage with crusts from nose, sinus infection, nose
bleeding, bloody phlegm, blood in urine, ear inflammation,

hearing problems, skin sore, rashes Wegener's granulomatosis =

Diagno: > ca | © rues
Tissue biopsy, upper respiratory tract biopsy, Gramlones .

histopathological examination, CRP, anti neutrophil
anemia, X ray, CT, MRI, biopsy to conform

Granulomatosis with an i

40. Si

Immune thrombocytopenia (ITP)
Common symptoms

IMMUNE > wa

THROMBOCYTOPENIA

An illness that can lead to bruising & bleeding. Low levels of
cells that help blood clot known as (platelets). It also known
as Idiopathic thrombocytopenia purpura cause purple
Peichae Purpura

bruises. ITP form low platelet count condition that keeps your
blood from clotting. It happen by immune system clears your
platelets from circulation.

Symptoms:

Petechiae: tiny red, purple dots on your lower legs resembles ras!
Purpura: red, brown larger that petechies, bruises, bleeding gums,

blood in stool, blood in urine, nose bleeding, heavy mensural periods,
hematoma, fatigue In

Diagnosis:
Physical examination, check for bleeding,
CBC, peripheral blood smear, platelet level

e

41. TREATMEN Sy

Although there is no Permanent cure for autoimmune disorders. Standar:
treatments aim to reduce signs & symptoms of disease.

Every ones immune system, genetics and environment are different. That
means that your treatment must be unique.
Some examples of medications used to treat autoimmune disease |

Pain killers
Anti Inflammatory drugs
Anxiety medication
Medication for depression
Rash creams

Insulin injection
Sleeping medications
Plasma exchanges

42. Corticosteroi
Pills

Herbs
Acupunture
Intravenous immune globulin
Drugs suppress immune system

Some other treatments includes:-
Medications: depending on type of autoimmune
Steroids: drugs often for Ist treatment because they work quié

Anti Inflammatory drugs: control and support organ functions
(painkillers, insulin shot)

Lifestyle changes: Shifts in personal habits as part of treatment, \ \
excercise or physical therapy are common for autoimmunity

43. PREVENTION

There is no prevention or preventive measure,

: but it may.
Take care e
of Jour body Experts recommend that to t #

Exercising consistently x

Staying away from cigarettes
Avoiding toxins we x
Eating a healthy diet

Limiting processed foods from your diet

44. \_ 4
REFERENCE

>https://my.clevelandclinic.org/health/disease/21624- autoimmune-diseases.

— https://primary immune.org/understanding-primary- Immuno/autoimmunity.
> https://slideplayer.com/slide/4900087/Systemic autoimmne diseases

> https:/Awww-Slideshare.net / Varugheseheorge! autoimmunity-89274283
>https:// Slede player. com/819d0/8764857/ autoimmune disorders.

> https:/Awww.webmd.com/atoz guides/auto. immune-diseases.
—https:/Avww.healthline.com/health/autoimmune-disorders #fa -qs.

—https:// med laephis-gor/ency/article/000816.htm.