Case 36: SLE

Question 1

how are large immune complexes cleared from the body?

Answer 1

large complexes are efficiently
cleared by binding to complement receptor 1 (CR1) on erythrocytes, which transfer
the immune complexes to the liver and spleen

there, they are removed from the
red-cell surface through interaction with a variety of complement and Fc receptors
on Kupffer cells and other phagocytes

Question 2

what is subacute bacterial endocarditis?

Answer 2

bacteria reside for a protracted period on the heart valves

this infection and subsequent inflammation damage the valve.

the antibody response to the prolonged presence of the bacteria is intense, and
immune complexes of IgG antibodies and bacterial antigens are formed

these complexes become trapped in the renal glomeruli and cause glomerulonephritis

the immunoglobulins in the immune complexes provoke the formation of anti-
IgG IgM antibodies known as rheumatoid factor

Question 3

what is mixed essential cryoglobulinemia?

Answer 3

it can become a chronic infection that provokes a marked IgG antibody
response, with the consequent formation of virus-containing immune complexes
and rheumatoid factor

the immune complexes can become entrapped in the renal
glomeruli as well as in small blood vessels of the skin, nerves, and other tissues,
where they cause inflammation of the blood vessels

the antibodies in
the virus-containing immune complexes precipitate in the cold = cryoglobulins

Question 4

what is SLE characterized by?

Answer 4

it’s characterized by the formation of antibodies against DNA and other
nuclear antigens

each day, millions of nuclei are extruded from erythroblasts in
the bone marrow as they mature into RBCs

this event,
among others, provides a rich source of DNA in those individuals prone to mounting
an immune response to DNA and subsequently developing SLE

Question 5

what lab result would suggest SLE?

Answer 5

if her blood at anti-nuclear antibodies (ANA)

also low serum C3 levels

Question 6

what is the treatment for SLE?

Answer 6

hydroxychloroquine sulfate

avoid direct sunlight

apply sunscreen

prednisone

naproxen to help with swelling

Question 7

which antibodies do people with SLE have?

Answer 7

they usually have antibodies
against multiple autoantigens, including double-stranded DNA (50%), histones,
and small ribonucleoproteins (30%)

some anti-DNA antibodies may cross-react with brain antigen, causing the neuropscychiatric
problems seen in some SLE patients

Question 8

where do most immune complexes in SLE get trapped?

Answer 8

kidney

these immune complexes fix complement and instigate injury to the kidney, joints, and other
organs

some anti-DNA antibodies are negatively charged and thus bind to basement membranes like in the kidney and form in situ immune complexes = inflammation

Question 9

what causes SLE?

Answer 9

1. some people have complement deficiencies in C1q or C4
2. genetic predisition indicated by the presence of several SNPs
3. hormones (women are 90% of SLE patients)

Question 10

which cytokine is associated with SLE?

Answer 10

INFα

T cells secrete INFα which is important in suppressing viral replication

INFα promotes the activation of autoreactive T cells and augments class switching and
antibody production in B cells

people on INFα treatment develop lupus

Question 11

Why do you think Nicole’s serum C3 was measured, both on her first visit to
the hospital and after therapy?

Answer 11

the serum levels of complement proteins C3 and C4 are lowered in SLE by the large
number of immune complexes binding C3 and C4, triggering their cleavage

the
depletion of these proteins is therefore proportional to the severity of the disease!

successful immunosuppressive therapy is reflected in an increase in the serum levels
of C3 and C4

measurement of either C3 or C4 is sufficient; it is not necessary to measure
both, and C3 is most usually measured

Question 12

What are the direct and indirect Coombs tests, and what did they tell us in
this case?

Answer 12

The objective of these tests was to establish whether Nicole had autoimmune hemolytic
anemia, which occurs in SLE when there are antibodies against erythrocytes

Question 13

Why was Nicole told to avoid direct exposure to sunlight?

Answer 13

because ultraviolet light provokes the onset of SLE and causes relapses

we don’t know why UV light does this

Question 14

Repeated analysis of Nicole’s urine was negative. What does this mean?

Answer 14

she had not developed glomerulonephritis

if she had, her urine would have contained
protein and red blood cells

Question 15

Nicole had a serum IgG level of 2020 mg dl–1. This substantially elevated level
of IgG is commonly found in patients with SLE. How could you explain this? And
what would you expect to find if we took a biopsy of Nicole’s swollen lymph nodes?

Answer 15

as a result of the constant stimulation of their B cells by autoantigens, patients with
SLE have a greatly expanded B-cell population and consequently an increased number
of plasma cells secreting immunoglobulin

alymph node biopsy from Nicole
would have exhibited follicular hyperplasia in the cortex and increased numbers of
plasma cells in the medulla

Question 16

The antigen in the immune complexes formed in SLE is often a complex antigen,
such as part of a nucleosome or a ribonucleoprotein particle, which contains
several different molecules. Patients often produce autoantibodies against each of
these different components. What is the reason for the production of this variety
of autoantibodies, and what type of failure in tolerance could be responsible for
autoantibody production?

Answer 16

in the first place, a large multimolecular complex such as a nucleosome carries many
separate epitopes, each of which can stimulate antibody production by a B cell specific
for that epitopes

any of these antibodies can bind the nucleosome particle to
form an immune complex

such potentially autoreactive B cells probably exist normally
in the circulation but, provided that T-cell tolerance is intact, they are never
activated because this requires T cells to be reactive against the same autoantigen

SLE is probably caused by a failure of T-cell tolerance – T cells for each of the components
of the complex antigen will not be needed to induce antibodies against its
individual components

Fig. A36.6 shows, a T cell that is specific for one protein
component of a nucleosome could activate B cells specific for both protein and DNA
components

Question 17

how are autoantibodies against
various components of a complex
antigen stimulated by an
autoreactive helper T cell of a single
specificity?

Answer 17

in SLE, patients often
produce autoantibodies against all of the
components of a nucleosome, or of some
other complex antigen

the most likely
explanation is that all the autoreactive
B cells have been activated by a single
clone of autoreactive T cells specific
for a peptide of one of the proteins in
the complex

a B cell binding to any
component of the complex through its
surface immunoglobulin can internalize
the complex, degrade it, and return
peptides derived from the relevant protein
to the cell surface bound to class II MHC
molecules, where they stimulate helper
T cells – these, in turn, activate the B cells

the figure illustrates this scheme for a
T cell specific for the H1 histone protein of
the DNA:protein complex comprising the
nucleosome, and two B cells specific for
the histone protein and double-stranded
DNA, respectively