IMMUNE II
Autoimmune Diseases
•
Rheumatoid arthritis
•
Sjogren syndrome
•
Systemic Lupus Erythematosus
•
Systemic sclerosis/ Scleroderma
•
>Inflammatory myopathies
•
>Mixed CT disease
•
>Polyarteritis nodosa
Others
1.
2.
3.
Inflammatory Myopathies
Mixed Connective Tissue Disease
1. High titers of anti U1 RNP
2. Low incidence of renal disease
3. Good response to
corticosteroids
PAN and other vasculitides
1. Noninfectious necrotizing
vasculitis
Immunologic Deficiency
Syndrome

Can be:
o
o
Primary immunodeficiency
Secondary immunodeficiency
PRIMARY IMMUNODEFICIENCY
1.
X linked agammaglobulinemia of
Bruton
 failure of precursor B cells to mature (Btk
gene)
 Males are affected, disease is seen at 6
months
 Recurrent URTI (bacterial); GI problems
(viral); G. lamblia; arthritis
 B cells are absent or decreased
 T cell mediated reaction are normal
 Mutation of Bruton tyrosine kinase (Btk)
encoded by gene in the long arm of X
chromosome at Xq21.22
Note:
Defects in the Bruton tyrosine kinase (BTK) gene
cause agammaglobulinemia. Agammaglobulinemia is
characterized by failure to produce mature B
lymphocyte cells and is associated with a failure of Ig
heavy chain rearrangement. Two thirds of cases are
familial, and one third of cases are believed to arise
from new mutations. Mutations of the BTK gene are
found in approximately 80% of patients with
agammaglobulinemia.
Prepared by: EGBII; 8-19-11
2. Common Variable Immunodeficiency
 Hypogammaglobulinemia usually affecting
all ab classes but sometimes only IgG
 Both sexes affected
 Occurs later in childhood/adolescence
 Similar manifestations
 Risk of lymphoid malignancy; gastric
cancer
3. Isolated IgA deficiency
 Common; Low levels of IgA in serum and
secretion
 Increase frequency of Autoimmune dse
 Sinopulmonary infections and diarrhea
4. Hyper-IgM Syndrome
 T cell disorder; mutation at CD40
 IgM is normal to increased but deficiency
of IgG, IgA and IgE
 Reccurent pyogenic infections and
Pneumocystis
5. Di George Syndrome
 T cell deficiency – failure of development
rd
th
of the 3 and 4 pharyngeal pouch
 Deletion of Chromosome 22q11
 Congenital defects: heart, BV, mouth, ears,
facies
 Poor defense against viruses and fungal
6. Severe Combined Immunodeficiency dse
 Both humoral and cell mediated
 Infants – thrush, diaper rash and failure to
thrive
 Infections to Candida, P. carinii,
pseudomonas etc
 Most common: x-linked; defect yc of
cytokine receptor, others are AR – defect
in ADA
 Histologic: thymus hypoplasia and other
lymphoid tissue
 Treatment: BM transplantation
7. Wiskott Aldrich Syndrome
 X linked, recessive; Thrombocytopenia,
eczema, recurrent infections, early death
 WASP gene
 Thymus – normal, secondary T cell
depletion in PB and T cell zones
 Low IgM; N IgG; high IgA and IgE
 Prone to develop malignant lymphoma
8. Genetic Deficiencies of the Complement
System
 C2 deficiency– SLE like autoimmune dse





 Most common
Properdin and factor D deficiency
C3 deficiency – pyogenic infections and IC
mediated GN
C56789 – neisserial infections
C1 – hereditary angioedema
 d/t release of vasoactive
peptides
Paroxysmal nocturnal hemoglobinuria
SECONDARY IMMUNODEFICIENCY
AIDS





Caused by retrovirus HIV
Signs & siymptoms:

Opportunistic infections,

secondary neoplasm and

neurologic Manifestations
Epidemiology

Homosexual and bisexual men
(>50 %)

IV drug abusers (20%)

Hemophiliacs (0.5%)

Recipients of blood/blood
components (1%)

Heterosexual contacts (10%)
Children under 13: 90% M-I transmission;
10% hemophiliacs etc
3 major ROT:
1. Sexual – 75%; virus is carried in semen, vaginal
secretion and cervical cells
2 ways:
 direct inoculation in BV and
 into dendritic cells or CD4+ cells



Etiology: Properties of HIV


Retrovirus – family Lentivirus
2 forms:

HIV 1 – US, Europe and Central
Africa

Most common in
Philippines

HIV2 – West Africa and India
Can be :
Male –to-male
Male-to-female
Female-to-male
2. Parenteral transmission
A. IV drug abusers
B. hemophiliacs – factor VIII and XI conc.
C. random recipients of blood transfusion
3. Mother-Infant transmission
A. In utero by transplacental route
B. During delivery – infected birth canal
C. After birth by ingestion of breast milk


Cannot be transmitted by casual
personal contact
Seroconversion afer needle stick accident
(health workers)  0.3%
HIV STRUCTURE:

Lipid envelope & core

Core:
o
Major capsid protein (p24)

Test against this*
o
Nucleocapsid protein (p7/p9)
o
2 copies of genomic RNA (gag,
pol, env genes)
o
3 viral enzymes (protease,
reverse transcriptase, integrase)
* Dendritic cells of mucosa express CCR5
HIV life cycle

Viral attachment

Viral penetration/ fusion

Uncoating

Reverse transcription

Nuclear entry

Integration/ RNA transcription

Protein Synthesis/ Protease cleavage

Viral assembly/ Budding
Pathogenesis

2 major targets:
1. Immune system, primarily cell mediated immunity
 Loss of CD4+T cell and Helper T cells
 Macrophages and dendritic cells
2. Central Nervous system

CNS involvement:
o
Infects macrophages & microglia
o
HIV carried by monocytes to the
brain
o
Neurons not infected
o
Indirectly caused by viral
products & sol Fs from infected
microglia
Life Cycle of HIV

CD4 molecules has a high affinity receptor
for HIV(gp 120)

Gp120 must bind to co-receptors (CCR5
and CXCR4)


CCR5 – M tropic strains
 Macrophages, monocytes and
freshly isolated blood T cells but
not in vitro propagated T cells
 Acutely ill patients – 90% of
cases are M tropic
CXCR4 – T tropic strains
 Over the course of infection T
tropic accumulate
 More virulent and cause final
rapid phase of disease
progression
Prepared by: EGBII; 8-19-11
Mechanism of T cell Immunodeficiency

Productive infection and viral replication in
infected cells – cause lysis of CD4+Tcells

1-2 billion T cells die a day
How they die
1. Activation induced cell death
2. Loss of immature precursors of
CD4+Tcells
3. Fusion of infected and uninfected cells with
formation of giant cells
4. Apoptosis of uninfected T cells




Hallmark of AIDS – marked reduction in
CD4+T cell
Latent infection of T cells can remain in
cells for months to years (0.05% of resting
CD4+T cells in the LN)
CD4+T cells produce cytokines: IL2, IL4,
Il5, IFN, MCF and hematopoeitic GF.
Major abnormalities in immune function –
table 6-12
HIV Infection of Non-T Cells

Macrophages and monocytes found in
tissues

Aspects of Macrophage infection

Infect/multiply in terminally
differentiated Macrophages due
to vpr gene

reservoir of infection

Gatekeepers of infection

Dendritic cells – mucosal and follicular

Abnormality in B cell function

Hypergammaglobulinemia due
to polyclonal B cell activation

Reinfection with CMV
and EBV

Gp 41 promotes B cell
growth

HIV infected
macrophages produce
IL6
Despite B cell activation – humoral immunity is
impaired; disseminated infection by encapsulated
bacteria: S pneumonia and H. influenzae
CNS Involvement

Macrophages and microglia

HIV is carried by monocytes to the brain

Neurons not infected

Damage is caused by viral products
produced by infected microglia: IL1, TNF,
IL6,
Nitric oxide
Course of HIV Infection (phases)

Acute retroviral syndrome

Middle, chronic phase
o
Most are asymptomatic

Clinical AIDS
o
Breakdown of host defenses
Clinical Features

Fever, weight loss, diarrhea,
lymphadenopathy

Opportunistic infections

P/jiroveci

Candidiasis

Mycobacteria

cryptococcosis

Neurologic disease

High incidence of tumors

Kaposi sarcoma

Non Hodgkins B cell lymphoma

Cervical cancer

Anal cancer
Opportunistic Infection

Herpes simplex

Pneumocystis Carinii
HIV -?

Encephalitis

CNS Lymphoma
Effects of Antiretroviral Drug Therapy on the
Clinical Course of HIV

new antiretroviral drugs target viral reverse
transcriptase, protease, and integrase

given in combination to reduce the
emergence of mutants that develop
resistance

Despite dramatic improvements, several
complications associated with HIV infection
and its treatment emerged

antiretroviral therapy develop a paradoxical
clinical deterioration

Deterioration even if CD4+ T cell increased
and viral load decreased

Immune reconstitution
inflammatory syndrome

Prognosis of AIDS remains dismal
Rejection of Tissue Transplants




Mechanisms of Recognition and Rejection
of Allografts
complex process both cell-mediated
immunity and circulating antibodies play a
role
recipient’s immune system recognizes the
graft as foreign & attacks it
2 mechanisms:

T-cell mediated mreactions

Antibody mediated reactions
T-cell mediated reactions

Cellular rejection

Destruction of graft cells by CD8+ CTLs &
delayed hypersensitivity (CD$+ helper
cells)

2 pathways of recognition
o
Direct
o
Indirect

DIRECT
o
T4 cells of recipient recognize
allogenic (donor) MHC
molecules on APCs in the graft

INDIRECT
o
Recipient T4 lymphos recognize
MHC antigens of graft donor thru
the recipient’s own APC
Antibody mediated reactions

Humoral rejection

2 forms
o
Hyperactue

(+) preformed
antidonor antibody in
recipient’s circulation
o
Acute

Unsensitized recipient

“Rejection vasculitis”
RENAL TRANSPLANT REJECTION
3 modes:

Hyperacute (minutes to hours)
o
Preformed antidonors antibodies
o
Endothelial damage, fibrinoid
necrosis

Acute (w/in days to months/ years)
o
Humoral (vasculitis)
o
Cellular (mononuclear infiltrates)

Chronic
o
Progressive renal failure,
vascular changes
LIVER TRANSPLANT REJECTION

Acute rejection
o

Within 2 months, mixed
inflammation in portal & central
veins
Chronic rejection
o
Inflammation, portal fibrosis,
arteriolar thickening, bile
ductular necrosis
HEART TRANSPLANT REJECTION

Acute cellular rejection
o
Lymphos, fiber necrosis

Acute vascular rejection
o
Ig deposition in small arteries
o
Vasculitis
BONE MARROW TRANSPLANT
W problems:

Immunodeficiency

Graft versus Host disease (GVHD)
o
Donor lymphocytes attack
recipient HLA antigens (deficient
lymphos)
o
ACUTE – affects immune
system, skin epithelia, liver,
intestine
o
CHRONIC – extensive
cutaneous injury
Amyloidosis




Amyloid – proteinaceous substance
deposited between cells
Amyloidosis – group of diseases having in
common deposition of similar appearing
proteins.
Physical nature – continuous non
branching fibrils
Chemical nature –

95% fibril protein;

5% P component and

glycoprotein; AL, AA, AB
3 most common
1. Amyloid light chain (AL) –
1. from PC contains Ig light chains
from plasma cells;
2. deposition is associated with
monoclonal B cell proliferation
2. Amyloid fibril protein (AA) –
1. non Ig, derived from liver;
2. circulates with HDL3,
3. Beta-amyloid (AB) –
1. found in Alzheimer disease
Other proteins found

transthyretin

B2-microglobulin
Prepared by: EGBII; 8-19-11

Prion protein – misfolded (CNS)
*Classification (Table 6-15: Systemic and Localized)


2 general categories of CHONs:

NORMAL CHONs
o
Within inferent tendency to fold
improperly & form fibrils when
production is increased

MUTANT CHONs
o
Prone to misfolding &
aggregation
Classification

Systemic
o
Primary
o
Secondary

Localized
SYSTEMIC – PRIMARY

Immunocyte dyscrasias with amyloidosis
o
Most common form (some forms
of plasma cells dyscrasias eg.
Multiple myeloma)

Reactive
o
Rheumatoid arthritis, heroin
abuses, renal cell CA, hodgkin’s
lymphoma

Hemodialysis associated
o
Deposition of B2 microglobulin in
synovium joints or tendon
sheaths (carpal tunnel
syndrome)

Heredofamilial
o
Rare, most common AR, familial
mediterreanea fever, elevated
IL-1, gene for pyrin
o
AD – deposits on peripheral &
autonomic nerves
(polyneuropahies)
LOCALIZED

Involves single organ or tissue

ENDOCRINE
o
Thyroid – medullary CA
o
Pancreas – islet tumors
o
Pheochromocytoma
o
Undifferentiated stomach CA

AGING
o
Senile systemic amyloidosis
(elderly)
o
Senile cardiac amyloidosis
o
Restrictive CMP & arrhythmias
Common ORGANS involved

Kidney – most common, most serious

Spleen – “sago spleen”; lardaceous spleen

Liver – total parenchymal replacement
Heart – major organ involved in senile
cases
Others
o
Adrenal, thyroid, pituitary, GIT
(macroglossia)
PATHOGENESIS

Related to abnormal CHON folding

Systemic disease that may involve
components of the immune system (only
some forms of amyloidosis)

Clinical recognition – appropriate biopsy
specimen
o
H&E stain – amorphous hyaline
extracellular
o
Differential stain: Congo red

Greenish bifrengence
with polarizing
microspore)