Chapters pdf - Roben - Muhadharaty

IMMUNOPATHOLOGY

This is concerned with the pathological changes that occur in the tissues as a result of improper immune
response. Body immune responses are normal defense mechanisms designed to combat the effect of invasion by
various environmental factors such as microorganisms & toxic chemicals. It usually works effectively, but
diseases may result from

1.  Inadequate immune response.
2.  Excessive immune response.
3.  Inappropriate immune response.

Inadequate immune responses:
These can result from immuno-deficiency states. There are two classes of immunodeficiency syndromes:

1. Primary; which is present at birth & often the result of a genetic disorder. (Fig. 6-1)
2. Secondary; which is much more common than the primary. It can be secondary to

a. Drugs
b. Diseases

(Fig. 6-2)

Primary immunodeficiency
X-linked agammaglobulinemia (Bruton disease)
This  is  one  of  the  more  common  forms  of  primary  immunodeficiency.  It  is  due  to  failure  of  pre-B-cells  to
differentiate into B-cells that results in the absence of gamma globulin in the blood (agammaglobulinemia). The
disease is seen primarily in males.  In most cases, there are recurrent bacterial infections. For obscure reasons,
auto-immune diseases (such as SLE & dermatomyositis) also occur in up to 20% of patients.
Isolated IgA-deficiency
This  is  the  most  common  of  all  primary  immunodeficiency  states.  There  is  marked  reduction  in  the  level  of
serum IgA but other immunoglobulins are normal. In most cases it is asymptomatic & detected accidentally, but
some  patients  have  recurrent  respiratory  infections  &  diarrhea.  There  is  also  a  significant,  unexplained
association with autoimmune diseases.
Hyper-IgM syndrome
In  normal  immune  responses  to  protein  antigens,  IgM  &  IgD  antibodies  are  produced  first,  followed  by  the
sequential  elaboration  of  IgG

IgA, & IgE antibodies. This orderly appearance of antibody types is called

isotype switching & is important for generating classes of antibodies that can effectively activate complement
&/or opsonize bacterial pathogens. Patients with this syndrome produce normal or even above normal levels of
IgM antibodies to antigens but fail to produce other antibody classes (IgG, IgA, or IgE isotypes).
Thymic hypoplasia (DiGeorge syndrome)
Affected infants  show failure of T-cells  to  form,  with  hypoplasia of  the thymus  gland; the  result  of failure of
development of the third and fourth pharyngeal pouches. The latter structures normally give rise to the thymus,
parathyroid glands, & portions of the face & aortic arch. Thus in addition to the thymic & T-cell defects, there
may  be  parathyroid  gland  hypoplasia  resulting  in  hypocalcaemia  and  tetany,  with  facial  abnormalities  that
include cleft lip and palate and congenital cardiac malformations. In 90% of cases there is a deletion affecting
chromosome 22q11. Transplantation of thymic tissue has successfully treated some of these infants.
Severe combined immune deficiency (SCID)
This condition may be inherited as a recessive disorder either autosomal or an X-linked. The condition is due to
failure  of  development  of  both  B-cell  &  T-cell  precursors  from  primitive  stem  cells.  Therefore  the  thymus  is
small or absent & lymphoid tissues in lymph nodes & gut are also greatly reduced. Children present early in life
with  recurrent  infections  including  candidal  thrush,  pneumonia  &  diarrhea.  There  is  a  very  low  blood
lymphocyte count & low blood immunoglobulin levels.

Acquired immunodeficiency syndrome (AIDS)
AIDS is a retroviral disease caused by human immunodeficiency virus (HIV) & is characterized by
1. Profound immuno-suppression leading to opportunistic infections
2. Secondary neoplasms
3. Neurological manifestations.
It is a worldwide disease. About 22 million people have died of AIDS since the epidemic was recognized some
20  years  ago;  3  million  people  died  in  the  year  2000  alone.  On  the  basis  of  serologic  data,  an  estimated  35
million  people  are  infected  with  HIV  (roughly  1  in  every  100),  including  1.4  million  children  &  17  million
women. AIDS represents the fifth most common cause of death in adults (25-44 years of age) in USA.
Epidemiology:
Transmission  of  HIV  occurs  under  conditions  that  help  the  exchange  of  blood  or  body  fluids  containing  the
virus or virus-infected cells. Thus, the three major routes are

1.  Sexual contact
2.  Parenteral inoculation
3.  Passage of the virus from infected mothers to their newborns.

Epidemiologic studies have identified five groups at risk for developing AIDS

1.  Homosexual or bisexual males (46% of reported cases).
2.  Intravenous drug abusers (25% of all patients).
3.  Heterosexual contacts of members of other high-risk groups (11% of patients).
4.  Recipients  of  blood  &  blood  components  (but  not  hemophiliacs)  who  received  transfusions  of  HIV-

infected whole blood or components (e.g., platelets, plasma) (1% of patients).

5. Hemophiliacs, especially those who received large amounts of factor VIII or IX concentrates (less than

1% of all cases).

The epidemiology of HIV infection &  AIDS is  different in  children (<13  years age).  About 1%  off all  AIDS
cases occurs in this population, 90% of them result from transmission of the virus from mother to infant, while
the remaining 10% are hemophiliacs & others who have received blood or blood products.
Sexual Transmission
Sexual  transmission  is  clearly  the  predominant  mode  of  infection  worldwide.  The  virus  is  present  in  semen,
both  extra-cellularly  &  within mononuclear inflammatory  cells,  &  enters  the recipient's body through tears or
abrasions in the genital mucosa.
Parenteral Transmission
Parenteral transmission of HIV is seen in three groups:

1.  Intravenous drug abusers
2.  Hemophiliacs receiving factor VIII or IX concentrates
3.  Random recipients of blood transfusion.

Among intravenous drug abusers, transmission occurs through shared needles and syringes contaminated with
HIV-containing blood. This group represents the main line

in the transmission of HIV to other adult population

through heterosexual activity.
Mother-to-infant transmission (vertical transmission)
This is the major cause of pediatric AIDS. Three routes are involved:

1.  In utero (transplacental spread)
2.  Intra-partum, (during delivery)
3.  Via ingestion of HIV-contaminated breast milk.

HIV infection cannot be transmitted by casual personal contact in home, workplace, or school, & there is no
convincing evidence for spread by insect bites.

Etiology
AIDS is caused by HIV. This is a human retrovirus belonging to the lentivirus family. Two genetically different
but antigenically related forms of HIV, called HIV-1 & HIV-2, have been isolated from patients. HIV-1 is the
more common type in USA, Europe & central Africa, whereas HIV-2 is commoner in West Africa. HIV-1
virion is spherical & contains α cone-shaped core surrounded by a lipid envelope derived from the host cell
membrane (Fig. 6-3). The virus core contains:

1- The major capsid protein P

2- Nucleocapsid protein P

3- Two copies of genomic RNA
4- The three viral enzymes (protease, reverse transcriptase & integrase).

is the most readily detectable viral antigen useful in the diagnosis of HIV infection in blood screening. The

viral core is surrounded by a matrix protein called P

. The viral envelope is studded by two viral glycoproteins

(gp

120

& gp

) critical for HIV infection of cells. The highly effective anti HIV-1 protease inhibitor drugs

prevent  viral  assembly  by  inhibiting  the  formation  of  mature  viral  proteins.  In  addition  there  are  other
regulatory  genes,  the  products  of  which  are  important  for  HIV  pahtogenicity,  &  a  number  of  therapeutic
approaches  are  being  developed  to  block  their  actions.  Molecular  analysis  of  different  viral  isolates  reveals
considerable  variability  in  many  parts  of  the  HIV  genome.  Most  variations  cluster  in  certain  regions  of  the
envelope  glycoproteins.  Because  the  immune  response  against  HIV-1  is  targeted  against  its  envelope,  such
extreme variability in antigen structure poses a barrier for vaccine development.

Pathogenesis
The two major targets of HIV infection are the immune system & the central nervous system.
Immunopathogenesis of HIV disease:
AIDS leads to severe impairment of the cell-mediated immunity system. Infection by HIV leads to destruction
of CD

lymphocytes & a decreased helper/suppressor T-cell ratio in the blood. The virus gains entry to T-cells

by attaching to surface CD

molecules. It takes over cellular metabolism to synthesize new virus. The CD

molecule is a high-affinity receptor for HIV. This explains the selective tropism of the virus for CD

+T-cells &

its ability to infect other CD

+cells, particularly macrophages & dendritic cells. However binding to CD

is not

sufficient for infection; the HIV envelope gp

120

must also bind to other cell surface molecules (co-receptors) to

facilitate cell entry (Fig. 6-4). The virus core containing the HIV genome enters the cytoplasm of the cell. The
viral genome then undergoes reverse transcription, leading to formation of complementary DNA (cDNA). In the
dividing T-cells, the cDNA enters the nucleus & integrates into the host genome. After integration, the provirus
may remain non-transcribed for months or years & the infection becomes latent; alternatively, proviral DNA
may be transcribed to form complete viral particles that bud from the cell membrane, leading to cell death (Fig.
6-5).

HIV colonizes the lymphoid organs (spleen, lymph nodes, and tonsils). Infected T-cells, macrophages, &
dendritic cells represent reservoirs of infection.
Initially, the immune system can vigorously proliferate to replace the dying T-cells, thus masking the massive
cell death occurring primarily in the lymphoid tissues. Due to loss of CD

+ cells, patients will have an inversion

of the CD

/CD

ratio in the peripheral blood; normally it is about 2, while in AIDS patients the ratio ≤ 0.5.

ADIS patients will also have qualitative defects in T-cell function.
Pathogenesis of central nervous system involvement:
The  nervous  system  is  a  major  target  of  HIV  infection.  Macrophages  &  their  equivalents  in  the  CNS;  the
microglia, are mainly infected with HIV. The virus is mostly carried into the brain by infected monocytes. The
mechanism of HIV-induced damage of the brain remains obscure. It is believed that neurologic deficit is caused
indirectly by viral products & soluble factors e.g. cytokines produced by macrophages/microglia.
Clinical phases
There are four phases (Fig. 6-6)
1.  Primary infection (sero-conversion): after infection, a median time of 2 months elapses before antibodies

to HIV are detected in the blood. Rapid viral replication occurs in all organs (P

antigen is detectable in

blood), & an immune response develops, with increased number of virus-specific CD

+cytotoxic T-cells.

About 50% of patients develop an influenza-like illness, skin rashes or lymphadenopathy, associated with
transient fall in CD

+T-cells. This phase represents the early acute phase.

2. Asymptomatic phase (incubation period): it represents a stage of relative containment of the virus. The

immune  system  is  largely  intact,  but  there  is  continued  HIV  replication.  The  length  of  this  phase  is
uncertain,  it  can  last  for  years.  Patients  have  antibodies  to  HIV  in  blood,  are  infective,  can  transmit  the
disease, & are asymptomatic.

3. AIDS-related complex: the proportion of CD

infected cells increases, their function is partially impaired

& their numbers in blood fall to around 400 cells/µliter. It is associated with non-specific general malaise,
fever night sweats, weight loss & diarrhea. Persistent generalized lymphadenopathy is common, with
serological & hematological evidence of impaired cell-mediated immunity & reduced CD

+T-cells.

Superficial fungal infections are frequent & infections with pathogens as Salmonella & Haemophilus are
sever. Similarly, gynecological infections such as candidiasis & pelvic inflammatory disease are increased.
2 & 3 phases represent the chronic phase (middle phase), that may last 7 to 10 years. However, sometimes
rapid progression after 2 to 3 years happens.

4. AIDS (crisis phase): it represent the final phase with fully developed immunodeficiency characterized by

fever , fatigue , weight loss , generalized lymphadenopathy & diarrhea ; the CD

+cell count is below 500

cells/μL. The patients develop serious opportunistic infections, secondary neoplasms &/or neurologic
manifestations (so called AIDS-defining conditions), & the patient is said to have developed full-blown
AIDS. Also any individual with CD

+cell counts less than or equal to 200/ μL is diagnosed as having ADIS.

Opportunistic infections
These are responsible for about 80% of deaths in patients with AIDS.
1. Pneumocystis carinii pneumonia is the presenting feature in many cases.
2. Recurrent mucosal candidiasis
3. Disseminated cytomegalovirus infection (particularly enteritis & retinitis)
4. Herpes simplex; especially sever ulcerating oral & perianal infections
5.  Mycobacterium  tuberculosis  &  atypical  mycobacteria  (mycobacterium  ovium-intracellular),  usually
disseminated infections
6. Toxoplasmosis, which is the most common secondary infection of the central nervous system
7. Cryptococcal meningitis is also quite frequent.
8.  Cryptosporidium  or  isospora  belli  infections  are  often  the  cause  of  the  so  common  persistent  diarrhea.
However, bacterial pathogens such as Salmonella & Shigella species may also be seen.
Neoplasms
The basis of increased risk of malignancy is multifactorial and include
1. Profound defects in T-cell immunity
2. Dysregulated B-cell & monocyte functions
3.  Infections  with  known  viruses  e.g.  Human  herpes  virus  type  8,  EBV,  human  papilloma  virus  &  unknown
viruses.
Patients with AIDS have a high incidence of certain tumors as:
1.  Kaposi  sarcoma  (KS):  this  vascular  tumor  is  the  most  common  neoplasm  in  AIDS  patients.  It  is  more

common among homosexual and heterosexual males than in intravenous drug abusers or other risk groups.
KS  in  AIDS  patients  is  usually  multicentric  &  tends  to  be  aggressive.  It  can  affect  the  skin,  mucous
membranes,  GIT,  lymph  nodes,  &  lungs.  KS  is  associated  with  human  herpes  virus  8  infections  in  AIDS
patients.  Non-Hodgkin  lymphomas:  the  second  most  common  neoplasm  in  AIDS  patients.  These  tumors
are highly aggressive, & involve many extra-nodal sites, commonly the brain; so primary lymphoma of the
brain is considered as an AIDS-defining condition. 30%-40% of these lymphomas are associated with EBV
infection.

2. Cervix uteri carcinoma: this due to human papilloma virus infection in ADIS patients. This virus is

intimately associated with squamous cell carcinoma of the cervix & its precursor lesions (cervical dysplasia
& carcinoma in situ); therefore, gynecologic examination should be routinely done for HIV-infected
women.

Central nervous system involvements:
This  is  common  in  AIDS  patients.  40%-60%  of  patients  have  clinically  evident  neurologic  dysfunction.  In
addition  to  opportunistic  infection  &  neoplasms,  patients  may  have  a  progressive  encephalopathy  clinically
called AIDS-dementia complex.
Vaccine
Molecular  analyses  have  revealed  an  alarming  degree  of  polymorphism  in  viral  isolates  from  different  AIDS
patients;  this  renders  vaccine  development  more  difficult.  In  addition,  the  nature  of  the  protective  immune
response is not yet fully understood. Therefore, at present prevention & effective public health measures remain
the mandatory in the fight against AIDS.

Inappropriate immune response:
Transplant rejection:
Organ transplantation is used increasingly to treat irreversible diseases of the kidney, liver, heart, lung, & bone
marrow.  Unfortunately,  the  action  of  the  immune  system  of  the  recipient  can  lead  to  destruction  of  the
transplanted  tissue  a  process  termed"  transplant  rejection".  This  is  a  complex  immunologic  phenomenon
involving  both  cell  -&  humoral-mediated  hypersensitivity  responses  of  the  host,  directed  against
histocompatibility antigens, human leukocytes antigens (HLA) on the donor allograft. The endothelial cells that
line the blood vessels of the graft are particularly rich in both HLA & blood group antigens, thus blood vessels
are important targets of the host's immune response to a transplanted allograft.

Patterns of transplant rejection:
Rejection reactions have been classified as

1.  Hyperacute
2.  Acute
3.  Chronic

The changes  are described in  the  context  of renal  transplants; however, similar changes  are seen  in  any  other
vascularized organ transplant.
Hyperacute rejection:
This occurs within a very short time from the moment the organ is perfused by the host's blood (minutes to a
few hours). In this form there is a widespread intravascular thrombosis in small vessels, with focal necrosis. It is
the result of pre-formed humoral host antibodies reacting with antigens in the graft. These preformed antibodies
developed due to
1. Previous rejection of a transplant
2.  Multiparous  women  who  develop  anti-HLA  antibodies  against  paternal  antigens  shed  from  the  fetus  (a
rejection in this instance will affect the transplanted organ donated by the husband and offspring)
3. Prior blood transfusions because platelets and WBCs are rich in HLA antigens and donors and recipients are
usually not HLA-identical.
Since  testing  recipients  for  the  presence  of  antibodies  to  donor  lymphocytes  become  a  routine  practice,
hyperacute  rejection  occurs  in  less  than  0.4%  of  transplants.  It  is  typically  recognized  grossly  by  the  surgeon
just  after  the  vascular  anastomosis  is  completed.  The  hyperacutely  rejected  kidney  rapidly  becomes  cyanotic,
mottled, & flaccid & may excrete only a few drops of blood-stained urine. In contrast to a non-rejected kidney
graft that regains a normal pink coloration & tissue turgor & promptly excretes urine. Histologically the rejected
kidney show acute arteritis & arteriolitis, vessel thrombosis & ischemic necrosis.
Acute rejection:
It  occurs  within  days  or  weeks  of  transplantation,  but  may  also  appear  after  cessation  of  immunosuppressive
therapy  that  is  given  to  the  recipient  to  prevent  rejection.  It  is  mediated  by  both  humoral  &  cell-mediated
mechanisms. Acute cellular rejection is mediated by T-cells reacting against donor HLA antigens, particularly
class II. It is accompanied by signs of renal failure. Histologically there is extensive interstitial CD

+ & CD

+T-

cell infiltration. The humoral component of acute rejection is characterized by vasculitis with endothelial
necrosis, neutrophils infiltration of vessel walls, & damage to the intima and elastic lamina of the larger arteries
in the graft.

Chronic rejection:
In  recent  years,  acute  rejection  has  been  significantly  controlled  by  immunosuppressive  therapy;  this  has
resulted in  the emergence of chronic rejection as  an important  cause of graft failure. Chronic rejection occurs
slowly & progressively after transplantation (months to years). It is the result of slow breakdown of the host's
tolerance  to  the  graft  and  may  be  due  to  inadequate  immune  suppression.  The  condition  is  manifested  by  a
progressive  rise  in  serum  creatinine  levels  (which  is  an  index  of  renal  dysfunction),  over  a  period  of  4  to  6
months. Histologically, there is intimal  fibrosis  mainly in  arteries  &  arterioles, leading to secondary ischemic
damage  to  the  parenchyma  manifested  by  hyalinization  and  loss  of  glomeuli,  interstitial  fibrosis,  &  tubular
atrophy. Chronic rejection does not respond to standard immunosuppressant regimens.
Complication of renal transplantation:
1.  Thrombosis of vascular graft
2.  Recurrence of original renal disease.
3.  Transplant rejections, hyperacute, acute or chronic.
Transplantation of other solid organs
Beside  the  most  frequent  kidney  transplantation,  transplantations  of  liver,  heart,  lungs,  &  pancreas  are  also
commonly  performed.  All  these  organs  transplantation,  unlike  that  of  the  kidney,  can  be  performed  with  a
disregard to histocompatibility typing. In transplantation of these organs instead we consider
1. ABO blood group typing
2. Absence of preformed circulating antibody
3. Body habitus (e.g. a child cannot receive a heart transplant from an adult).
Autoimmune diseases
Autoimmune  diseases  are  the  result  of  immune  reactions  against  self-antigens  i.e.  against  body  tissue  or
individual tissue components. Sometimes the immune response is an antibody response (autoantibody), or it is a
cell-mediated immune response.  In  autoimmune  diseases, the normal  mechanisms  ensuring tolerance for self-
antigens  have  broken  down.  (Self-tolerance  indicates  lack  of  immune  responsiveness  to  one's  own  tissue
antigens).  Some  autoimmune  diseases  have  a  genetic  component;  e.g.  certain  diseases  are  associated  with
particular  HLA  histocompatibility  types.  In  other  situations,  an  autoimmune  disease  can  be  triggered  by  a
microbial infection.
Mechanisms involved in the pathogenesis of autoimmune diseases
There  are  regulatory  mechanisms  that  present  normally  to  prevent  the  occurrence  of  autoimmune  diseases.
Failure of such mechanisms is responsible for the occurrence of such diseases in some 3% of the population that
suffer  from  such  diseases.  These  will  be  discussed  under  the  heading  of  immunological  tolerance  and  its
breakdown.
Immunological tolerance
Both  T-  and  B-cells  bear  self-reactive  molecules  (receptors)  that  can  recognized  self-antigens  and  react  with
them  to  produce  eventually  tissue  damage  and  this  is  the  essence  in  the  production  of  various  autoimmune
diseases. To avoid such incidents T- and B-cells bearing such molecules (receptors) must be either eliminated or
down-regulated so that the immune system is made specifically non-reactive i.e. tolerant to self antigens. Since
T-cells and in particular CD4+ T-cells, have a central role in controlling all immune responses, the process of T-
cell tolerance is much more important than B-cell tolerance in the avoidance of autoimmunity. This is because
not only T-cells may produce tissue damage directly but also self-reacting-B-cells will not be able to produce
auto-antibodies unless they receive appropriate T-cell help.
Processes  that  induce  specific  tolerance  arise  inside  the  thymus  (thymic  tolerance)  or  outside  the  thymus
(peripheral tolerance.
Thymic tolerance is achieved through eliminating all T-cells capable of recognizing self-proteins. This is not,
however, induced to many tissue-specific proteins.
Peripheral tolerance this involves several mechanisms
1.  Immunological  ignorance:  the  self-antigens  are  invisible  to  the  immune  system  either  because  of
sequestration of the antigen e.g. within the vitreous humour of the eye or because the self antigens are presented
to  the  CD4+  cells  in  low  levels  that  is  not  enough  to  activate  such  cells.  To  prevent  large  amounts  of  self-
antigen  from  gaining  access  to  antigen-presenting  cells  a  slow  gradual  tissue  breakdown  is  achieved  through
apoptosis.

2. Anergy: CD4+ T-cells requires two signals to become activated and initiate an immune response: an antigen-
specific signal through the T-cell antigen receptor and a second, nonspecific signal through interaction of CD4+
cells with antigen-presenting dentritic cells. Such an interaction is only likely to occur in secondary lymphoid
tissues such as lymph nodes i.e. the encounter of both cells is very restricted.
If no second signal is  available then stimulation through T-cell receptor alone leads  to  apoptosis  or a state of
longstanding unresponsiveness called anergy.
3.  Suppression;  self-reactive  T-cells  may  be  actively  suppressed  by  inhibitory  T-cells,  which  recognize  the
same  antigen  (suppressor  T-cells;  CD8+).  This  is  achieved  through  cytokines  produced  by  the  suppressor  T-
cells to inhibit nearby helper (CD4+) T-cells.
4.  B-cell  tolerance:  this  is  less  complete  than  T-cell  tolerance.  The  production  of  self-reactive  antibodies  by
these B-cells is limited mainly by the lack of T-cell help for cell antigens.
Breakdown of tolerance
For autoimmune diseases to occur, the above mechanisms of immunological tolerance must be broken down.
1.  Overcoming  peripheral  tolerance;  resulting  from  excessive  access  of  self-antigens  to  antigen  presenting
cells, excessive nonspecific signaling, or alterations in which self-antigens are presented to the immune system.
All  these  are  likely  to  happen  when  inflammation  or  tissue  damage  is  present.  The  structures  of  the  self-
antigen’s  peptides  (self-peptides)  may  be  altered  by  viruses,  free  radicals  or  ionizing  radiation.  With  such
structural changes the previously established tolerance is bypassed. Tissue damage may release antigens that are
already  sequestrated  from  the  immune  system  e.g.  spermatozoa  &  ocular  antigens.  Post-traumatic  uveitis  &
orchitis (after vasectomy) probably result from immune responses against antigens normally sequestered in the
eye & the testis.
2.  Molecular  mimicry:  structural  similarity  between  self-antigens  and  microbial  antigens  may  trigger  an
immune  response.  In  systemic  infection,  this  cross  reactivity  will  cause  expansion  of  the  responsive  T-cell
population recognizing the self-peptide if local conditions allow. The process is known as molecular mimicry.
For  example,  rheumatic  heart  disease  sometimes  follows  Streptococcal  infection  because  antibodies  to
Streptococcal M protein cross-react with cardiac glycoprotiens.

Once tolerance has broken down, the resulting immunological mediated inflammation and tissue damage may
allow presentation of further peptides. The immune response broadens and local tissue damage accelerates. This
domino-like process is known as epitope spreading.
(Domino effect: by which one event triggers a succession of other, often similar, events, like a falling domino at
the beginning of a line of up-ended dominoes).

Etiology of autoimmune diseases
The  interaction  between  genetic  and  environmental  factors  is  important  in  the  pathogenesis  of  autoimmune
diseases.
Genetic factors
Family  studies  have  confirmed  a  genetic  contribution  in  all  autoimmune  diseases.  This  is  supported  by  the
findings that
1.  Different  autoimmune  diseases  may  cluster  within  the  same  family  (such  as  SLE,  autoimmune  hemolytic
anemia, & autoimmune thyroiditis).
2. Subclinical autoimmunity is common among family members.
The  genetic  contribution  to  autoimmune  disease  usually  involves  multiple  genes.  The  strongest  associations
between  genetic  factors  and  autoimmunity  involve  alleles  of  the  major  histocompatibility  complexes  (MHC).
This is because of central role of the products of many of these genes in the
1. T-cell function
2. Control of immunity and inflammation.
It is likely that the MHC class II alleles influence the presentation of autoantigenic peptides to T-cells.
An example of such a connection is the well-known strong association of HLA-B

with ankylosing spondylitis.

Genetic factors in autoimmunity:

Genetic factors play a significant role in the predisposition to autoimmune diseases. This is supported by the
following

1- There is familial clustering of several human autoimmune diseases Linkage of several autoimmune

diseases with HLA, especially class II antigens.

Environmental factors
These may trigger autoimmune diseases and include
1. Hormones
2. Infections
3. Drugs
4. UV radiation

Hormones
The contribution of hormones in the pathogenesis of autoimmune diseases is supported by the following
1.  Most  autoimmune  diseases  affect  females  much  more  commonly  than  males;  hormonal  factors,  besides
genetics, must play a major role in this gender difference.
2.  The  peak  age  of  onset  of  most  autoimmune  diseases  is  within  the  reproductive  years.  Evidences  implicate
estrogens as triggering factors.
3.  In  animal  models  removal  of the ovaries  inhibits the occurrence of  autoimmune diseases  (e.g.  SLE), while
estrogen administration accelerates the onset of the disease.
Infections
The  relationship  between  infection  and  autoimmunity  is  clearest  in  the  situation  of  molecular  mimicry.
Autoimmune diseases tend to be less common in parts of the world with high incidence of parasitic diseases and
other infections. This inverse relationship between the occurrence of autoimmune diseases and the incidence of
various infections is supported by experiments on animal models.
3. Drugs
Drug-induced autoimmunity may involve mechanisms comparable to molecular mimicry, whereby the drug or
drug-self  molecule  complex  has  a  structural  similarity  to  self  that  allows  bypassing  tolerance.  Drug-mediated
autoimmunity  affects  only  a  small  proportion  of  those  treated  and  is  probably  genetically  determined.  For
example,  HLA-DR2  is  associated  with  penicillamine-induced  myasthenia  gravis,  whereas  DR3  is  associated
with penicillamine-induced nephritis. Genetic variation in drug metabolism is also important.  Individuals who
are slow metabolizers of the offending drug are more prone to develop the disease (for e.g. drug-induced SLE)
than  rapid  metabolizers.  Slow  metabolism  of  the  offending  drug  may  give  more  time  for  the  formation  of
immunogenic conjugates between the drug and self-molecule.
4. Ultraviolet radiation
  Exposure  to  UV  radiation,  usually  in  the  form  of  sunlight  is  a  known  trigger  for  skin  eruptions
(photosensitivity skin eruption) and sometimes systemic involvement in patients with SLE.  UV radiation acts
in this context through two possible mechanisms
a. modifying self-antigens to become immunogenic
b. enhancing apoptosis (cell death) of the cells, which lead to cell surface expression of auto-antigens that are
usually  hidden  within  the  cell.  Such  exposure  of  the  antigens  leads  to  Ag-Ab  reaction  that  triggers  tissue
damage.

Autoimmune  diseases  may  be  either  organ  specific  (response  directed  against  a  single  component  of  a  single
tissue)  or  more  often,  a  non-organ-specific  autoimmune  disease  (response  directed  against  a  component  that
present in many tissues & organs throughout the body.

The organ specific autoimmune diseases are listed in following tables:

Organ

Disease

Associated
autoantibody

Comment

Skin

Vitiligo

Antityrosine Ab

Hypopigmentation

Thyroid

Grave's disease

thyroid-stimulating Ab
thyroid

growth-

stimulating Ab

Hyperthyroidism

Thyroid

Hashimoto's disease

Anti-thyroid

specific

Hypothyroidism

Adrenal cortex

Addison's disease

Anti-adrenal Ab

Hypoadrenocorticalism

Stomach

Autoimmune

(type

A) gastritis

Anti-intrinsic factor &
parietal cell Ab

Pernicious anemia

Pancreatic islet cells
(insulin-producing)

Type

diabetes

mellitus

Anti-islet

B-cell

(insulin) Ab

Diabetes mellitus

Skeletal muscle

Myasthenia gravis

Acetylcholine receptors
Ab

Muscle fatigue

Multi-organ involvement is frequently caused by secondary damage due to circulating immune complex. This
group of disorders is often collectively called the ''connective tissue diseases'' or ''collagen vascular
diseases''.

Disease

Main organ involved

Systemic lupus erythematosus

Skin , kidney , joints , heart , lung

progressive systemic sclerosis

Skin , gut , lung

Polymyositis- dermatomyositis

Skeletal muscle , skin

Rheumatoid disease

Joints , lungs , systemic vessels

Systemic lupus erythematosus (SLE):
SLE is an autoimmune disease and one of the ''connective tissue disorders''. It is a fairly common disease, with a
prevalence of 1:2500 persons. Like most autoimmune diseases, there is a strong female predominance (9:1) and
is  particularly  common  in  young  &  middle-aged  individuals.  Clinically,  the  disease  is  characterized  by
remissions & relapses, with an acute or insidious onset that may involve any organ in the body. Acute flare-ups
are  usually  controlled  by  steroids  or  other  immunosuppressive  drugs.  Renal  failure,  intercurrent  infections,  &
diffuse central nervous system involvement are the major causes of death.
Etiology & pathogenesis:
SLE  is  a  complex  disease  of  multifactorial  origin  including  genetic,  hormonal,  &  environmental  factors,
resulting in a T-cell & B-cell activation that leads to the production of several autoantibodies. The main defect
in  SLE  is  a  failure  to  maintain  self-tolerance.  Many  types  of  autoantibodies  can  be  identified  in  SLE  patient
particularly antinuclear antibodies (ANAs), which are directed against several  nuclear antigens.  ANAs can be
identified using the indirect immunofluorescence test, which is positive in virtually every patient with SLE, so
that  the  test  is  quite  sensitive.  However,  it  is  not  specific.  However,  the  presence  of  autoantibodies  against
double  stranded  DNA  is  diagnostic  to  SLE.  Antibodies  against  blood  cells,  including  red  cells,  platelets,  &
lymphocytes,  are  found  in  many  patients.  Antiphospholipid  antibodies  are  found  in  40%  to  50%  of  SLE
patients.  Because  phospholipids  are  required  for  blood  clotting,  SLE  patients  with  antiphospholipid  antibody
tend  to  have  venous  and  arterial  thrombosis,  thrombocytopenia  &  recurrent  spontaneous  miscarriages
(antiphospholipid syndrome).

Genetic factors:
There is much evidence supporting the genetic predisposition for SLE:

1. There is a higher rate of concordance in monozygotic twins (25%) than in dizygotic twins (1%-3%).
2. Family members have an increased risk of developing SLE, & up to 20% of clinically unaffected first-

degree relatives may have autoantibodies.

3. There is a positive association between SLE & class II HLA genes.
4. About 6% of SLE patients have inherited deficiencies of complement components. Lack of complement

may impair removal of immune complexes from the circulation & favor tissue deposition, resulting in
tissue injury.

Nongenetic factors:

1. The clearest example of environmental factors in initiating SLE is the occurrence of a lupus-like

syndrome in patients receiving certain drugs, including procainamide & hydralazine. Thus, most
patients treated with procainamide for more than 6 months develop ANAs, with clinical features
of SLE appearing in 15%-20% of them.

2. Sex hormones; the female predominance of SLE, reflects the important influence of sex

hormones in the development of the disease, due to the helpful effects of estrogens on antibody
synthesis.

3. Exposure to ultraviolet light exacerbates the disease in many individuals. Ultraviolet light may

damage DNA & promote cell injury that will release cellular contents & augment the formation
of DNA/antiDNA immune complexes.

Mechanism of tissue injury:
Most  of  the  visceral  lesions  are  caused  by  immune  complexes  (type  III  hypersensitivity).  For  example,
DNA/anti-DNA complexes can be detected in the glomeruli. In addition, autoantibodies against red cells, white
cells, & platelets causing effect by type II hypersensitivity. The denaturated nucleus of an injured cell will be
engulfed by a neutrophil or macrophage producing the LE cell. LE cell test is positive in about 70% of patients
with SLE.
Clinical manifestations:
The  clinical  presentation  of  SLE  is  so  variable  &  with  similarities  to  other  autoimmune  connective  tissue
diseases  (rheumatoid  arthritis,  polymyositis  &  others)  so  that  it  has  been  necessary  to  develop  diagnostic
criteria.  If  a  patient  has  four  or  more  of  the  criteria,  serially  or  simultaneously,  during  any  interval  of
observation, the diagnosis of SLE is established. The range of features that can occur in SLE is shown by the
American Rheumatism Association
List of Diagnostic Criteria for SLE

1.  Discoid skin rash.
2.  Malar rash.
3.  Photosensitivity.
4.  Oral ulcers.
5.  Arthritis.
6.  Serositis.
7.  Renal disorder.
8.  Neurologic disorder.
9.  Hematologic disorder.
10. Immunologic disorder.
11. Presence of antinuclear antibody.

Skin  rashes  of  various  types  occur  in  about  80%  of  all  patients  with  SLE.  One  of  the  most  common  tissues
affected in SLE is the skin. The most common patterns of skin rash are:
1.  Chronic discoid LE: round (discoid), red scaly telangiectatic plaques, usually on the face & scalp,
2.  Malar skin rash: a symmetrical, slightly raised red erythematous rash on the cheeks & across the bridge of

the nose (butterfly rash). This is seen in 50% of the patients.

3. Photosensitivity reactions: exposure to sunlight (ultraviolet light) exacerbates the erythema, & the rash will

be seen on the face & sun-exposed areas mainly. Direct immunofluorescence microscopy reveals deposition
of immunoglobulins (IgG, IgM) & complement at the dermo-epidermal junction. Histologically: there is

characteristic liquefactive degeneration of the basal layer of epidermis, edema at the dermo-epidermal
junction & mononuclear infiltrates around blood vessels & skin appendages. (Fig. 6-7)

4.  An acute necrotizing vasculitis: clinically, producing slightly raised erythematous patches.
5.  Oral mucosal lesions in SLE produce superficial erosions & ulcers.
6.  Musculoskeletal symptoms may be the earliest presenting feature of SLE. Joint pain and swelling occurs in

about 90% of patients.

7. Serositis: the pericardium & pleura are usually affected. In the acute phase they may lead to serous effusion.
8. Renal disorder: kidney involvement in SLE is common, & is an important cause of morbidity & mortality.

The severity of involvement can vary from minor abnormalities (such as asymptomatic albuminuria) to
sever glomerular disease leading to renal failure. The basis of the glomerular damage is the deposition of
immune complexes within glomeruli. (Fig. 6-8)

9. Neurological & psychiatric disorders are common in SLE.
10. Hematological abnormalities are common in SLE, some having an unknown cause, & others having an

autoimmune mechanism:

a.  Normocytic, hypochromic anemia.
b.  Autoimmune hemolytic anemia
c.  Leucopenia usually due to disproportionate reduction of lymphocytes (lymphopenia).
d.  Thrombocytopenia

The spleen may be moderately enlarged. Involvement of the heart showing mainly pericarditis, myocarditis  &
vascular lesions called Libman-Sacks endocarditis, which represent a nonbacterial verrucous endocarditis. (Fig.
6-9)

Systemic sclerosis (SS):
It is one of the connective tissue diseases, & affects many systems & organs. It is three times more common in
women than in men, & occurs mainly in middle-aged or elderly individuals. The main abnormality is an excess
formation of fibrous tissue, which leads to rigidity of the affected organ. Vessel wall thickening & perivascular
fibrosis are characteristic features in SS, & are responsible for slowly progressive ischemic damage in a wide
range  of  tissues.  The  skin  is  the  most  commonly  affected  organ  (scleroderma),  but  the  alimentary  tract,  lung,
kidney & heart may also be involved.
There is usually affection of the skin of the fingers & distal regions of the upper extremities. Extending to the
upper  arms,  shoulders,  neck  &  face  may  occur.  There  is  dermal  thickening  due  to  fibrous  replacement  of  the
normal dermal structures.

Rheumatoid disease (rheumatoid arthritis) (RA)
RA  is  a  multi-system  connective  tissue  disease  in  which  the  dominant  effects  are  on  the  joints.  It  is
characterized by the presence of a circulating autoantibody,  ''rheumatoid factors'' (seropositive arthritis). RA
is a very common condition, with a prevalence of about 1%.  It is three to five times more common in women
than in  men, & the usual  age of onset is  between 35 to  45  years. The disease is  not  limited to  joints  but  also
affects, among others, the skin, lungs, blood vessels, eyes & the hemopoietic system.

Pathologic changes:
RA  typically  presents  as  symmetric  polyarthritis,  mainly  affecting  the  small  joints  of  the  hands  &  feet.
However,  larger  joints  may  also  be  involved  e.g.  ankles,  knees,  wrists,  elbows  &  shoulders.  Classically,  the
proximal  interphalangeal  &  metacarpophalangeal  joints  are  affected.  The  affected  joints  become  swollen,
painful & warm, often with redness of the overlying skin. There are three main pathological changes

1. In the early stage there will be rheumatoid synovitis. The synovium is swollen with prominent villous

pattern. There is a great increase in chronic inflammatory cells mainly lymphocytes, plasma cells &
macrophages with formation of lymphoid follicles. There is marked synovial hypertrophy & hyperplasia,
often with increased vascularity due to angiogenesis. There is often fibrinous effusion in the joint space; the
fibrin gets deposited on the synovial surfaces.

2. With time there is articular cartilage destruction with replacement by vascular granulation tissue (pannus).

The latter grows across the surface of the articular cartilage from the edge of the joint.

3. The inflammatory pannus causes focal destruction of the subjacent bone; this is manifested as ''erosions'' on

radiographs. Following destruction of the articular cartilage & erosion of the subarticular bone, the pannus
fills the joints  space.   Subsequent  fibrosis  &  classification may cause permanent  ankylosis  of the affected
joint.  The  loss  of  articualr  cartilage  can  lead  to  secondary  osteoarthritis  (a  degenerative  joint  disease),
especially in the weight-bearing joints such as the knee. Destruction of tendons, ligaments, & joint capsules
produces deformities of the joints; that of the hand are characteristic, which include radial deviation of the
wrist,  ulnar  deviation  of  the  fingers,  &  flexion-hyperextension  abnormalities  of  the  fingers  (swan-neck
deformity).

Rheumatoid subcutaneous nodules develop in about 25% of the patients. They occur along the extensor
surface of the forearm or other areas subjected to mechanical pressure. Rheumatoid nodules are firm, nontender,
oval or rounded masses up to 2 cm in diameter. Microscopically there is central focus of fibrinoid necrosis
surrounded by a palisade of macrophages which is rimmed by granulation tissue.

Pulmonary  involvement  in  RA  takes  the  form  of  interstitial  pneumonitis  &  fibrosing  alveolitis,  which  leads
eventually  to  a  pattern  of  interstitial  fibrosis  called  ''honeycomb  lung''.  The  latter  is  also  caused  by  other
diseases such as systemic sclerosis.
Anemia is very common in rheumatoid disease as is increased susceptibility to infections, & sepses, which are
important & common causes of death.
Pathogenesis of RA:
There is a genetic predisposition to RA which is suggested by
1. The increased frequency of this disease among first-degree relatives.
2. The strong association of the disease with HLA-DR

&/or HLA-DR

About 80% of the patients have rheumatoid factors (RF) in their serum & synovial fluid. RF represents an
autoantibody mainly of IgM class directed against the Fc portion of IgG. RF & IgG form immune complex that
fix complement, attract neutrophils, & lead to injury by a type III hypersensitivity reaction.
It is proposed that the disease is initiated in a genetically predisposed individual, by activation of helper T-cells
possibly by microbial agent, the activated CD

+cells produce cytokines that will:

a. Activate macrophages & other cells in joint space to release degrading (proteolytic) enzymes & other

factors that initiate inflammation and cause tissue destruction.

b. Activate B-cells, which produce RF (autoantibody). These will form immune complexes with IgG that

often get deposited on the synovial membrane with subsequent joint injury.

c. It has been found that activated T-cells will also induce osteoclast cell differentiation & activation that

leads to bone resorption.

Juvenile rheumatoid arthritis (JRA):
It is a chronic idiopathic arthritis that occurs in children. Like the adult form of (RA) it is a destructive arthritis
but differs from it by the following points
1. It affects large joints
2. There is absence of RF
3. There are no rheumatoid nodules.
4. Some cases of JRA are associated with HLA-B

SjÖgren syndrome:
This autoimmune disease is characterized by dry eyes (keratoconjunctivitis sicca) & dry mouth (xerostomia)
resulting from immune-mediated destruction of the lacrimal & salivary glands. It occurs in two forms a primary
form i.e. an isolated disorder, and as a secondary form associated with other autoimmune disorder such as, RA,
SLE, polymyositis, systemic sclerosis, vasculitis and thyroiditis.

Inflammatory myopathies:
These are heterogeneous group of rare disorders characterized by immune mediated muscle injury &
inflammation. Under this heading are three disorders

1. Polymyositis
2. Dermatomyositis ,

3. Inclusion body myositis.

They may occur alone or with other autoimmune disease as systemic sclerosis.
Clinically, they present with symmetric muscle weakness initially affecting large muscles of the trunk, neck &
limbs, with difficulty in getting up from a chair. In dermatomyositis, there is associated skin rash that involves
the  upper  eyelids  together  with  &  periorbital  edema.  Histologically,  there  is  infiltration  of  lymphocytes  with
degeneration of muscle fibers.

Mixed connective tissue disease:
Patients present with multiple features suggestive of SLE, polymyositis,  & systemic sclerosis. They also have
high titer of antibodies to ribonucleoprotein antigen. Two distinctive features of this disease
1. The kidneys are rarely involved
2. An extremely good response to corticosteroids.

Polyarteritis nodosa (PAN):
It  is  a systemic disease  characterized by inflammatory necrosis  of the  wall of small-& medium-sized arteries.
The  clinical  effects  are  the  result  of  vessel  occlusion  leading  to  small  areas  of  infarction.  The  tissues  most
seriously affected are the kidneys, heart, alimentary tract, liver, CNS, peripheral nerves, skeletal muscle & skin.
The cause of the disease is unknown, but it is likely to be immune-complex-mediated. There is an association
with chronic hepatitis B virus antigenemia.

AMYLOIDOSIS
Amyloid  is  the  generic  term  for  a  variety  of  proteinaceous  materials  that  are  abnormally  deposited  in  tissue
interstitium causing clinical disorders.
Morphology
The  diagnosis  depends  on  identification  by  light  microscopy  of  the  material  in  biopsy.  H  &  E  stain  shows
amyloid as an amorphous, eosinophilic hyaline extracellular substance.
It also takes up certain special stains; the most widely known of these is congo red stain, which gives pink to
red  color  under  ordinary  light  microscopy  but  characteristically  green  birefringence  under  polarizing
microscopy. (Fig. 6-10)
Electron microscopy of amyloid shows that it is composed of fibrils in a ß- pleated sheet. (Fig. 6-11)
Effects
Progressive accumulation causes pressure atrophy at adjacent cells.
Composition
Amyloid is not a single chemical entity, thee major & several minor biochemical forms could be found.
Physical nature of amyloid
95% of  amyloid  component  is  nonbranching  fibrils,  7.5-10 nm  in  width,  with  characteristic  crossed β-pleated
sheet conformation.
The minor component is a nonfibrillar pentagonal glycoprotein (P-component) & proteoglycans, which form the
remaining 5%.

Chemical nature of amyloid:

1. AL (amyloid light chain) derived from plasma cell & contains Ig light chain. It is encountered with

some forms of monoclonal B-cell proliferation.

2. AA (amyloid- associated): derived from serum precursor protein synthesized by the liver (serum

amyloid associated) (SAA). It is non-immunoglobulin protein and deposited in the setting of chronic
inflammatory states.

3. Aβ: found in the cerebral lesions of Alzheimer disease.
4. Transthyretin (TTR), this is a normal serum protein that binds & transports thyroxin & retinol. It is

deposited in the heart of aged patients. A mutant form of TTR is deposited in some genetic disorders and
is called familial amyloid polyneuropathies.

5. ß

– microglobulin, this is a component of the MHC class I molecules & a normal serum protein.

Amyloidosis may be systemic (generalized) or may be localized to a single organ. Systemic amyloidosis may
be

1. Primary which is associated with immunocyte dyscrasia
2. Secondary as a complication at chronic diseases.

Primary amyloidosis

1. AL type, usually systemic. Examples include amyloidosis which is associated with multiple myeloma (a

malignant neoplasm of plasma cells). In this neoplasm two forms of AL are synthesized

a. Abnormal amount of specific immunoglobulin producing M (myeloma) protein spike on serum

electrophoresis.

b. λ & κ light chains known as Bence Jones protein which is excreted in urine.
2. Reactive systemic amyloidosis (AA): the distribution of the amyloid deposition in this pattern is

systemic. Previously this from was considered to be secondary because it is associated with chronic
infectious diseases like TB, bronchiectasis, chronic osteomyelitis. With the use of antibiotics to control
such infections, currently it tends to be associated with chronic inflammation caused by autoimmune
states such as rheumatoid arthritis and inflammatory bowel disease.

3. Heredofamilial amyloidosis (AA)

Examples include familial Mediterranean fever, which is an autosomal recessive febrile illness of
unknown cause, associated with serosal inflammation such as the peritoneum, pleura & synovium.

4. Localized amyloidosis (AL) limited to one organ or tissue that may produce detectable nodular masses

or be evident only through microscope examination.

5. Endocrine amyloid (TTR) this form is found in medullary carcinoma of the thyroid, islet cell tumor of

pancreas and pheochromocytoma.

6. Amyloid of aging (TTR) usually occurs in the age group 70-80 years and is called senile systemic

amyloidosis. The heart is predominantly involved.

Pathogenesis:
Long  standing  tissue  injury  &  inflammation  cause  macrophage  activation  &  lead  to  elevated  SAA  levels
through  the  influence  of  cytokines  (IL

, IL

) on liver cells. Elevation of SAA levels alone does not lead to

amyloidosis.  It  is  believed  that  SAA  is  normally  degraded  to  soluble  end  products  by  action  of  monocyte-
derived enzymes. So individuals who develop amyloidosis have an enzyme defect that results in the incomplete
breakdown of SAA, thus generating insoluble AA molecules.
Morphological effects on various organs
Kidneys become large, pale, gray and firm.
Amyloid is deposited in the glomeruli, peritubular tissue and in the wall of blood vessels. (Fig. 6-12)
Spleen becomes firm, enlarged, pale and waxy on cut section (Sago spleen).
Liver is enlarged, pale and waxy. The deposition occurs in the space of Disse and surrounding blood vessels.
Clinical correlation
S &S depend on site, amount & duration of the deposition.
Weakness,  fatigue,  &  weight  loss  are  the  most  common  initial  symptoms.  Later  the  manifestations  may  be
present as renal disease (nephrotic syndrome) which is often the major cause of symptoms in reactive systemic
amyloidosis.  Liver  involvement  is  associated  with  hepatomegaly.  Heart  involvement  may  lead  to
cardiomyopathy that is associated with arrhythmias.