Goodpasture syndrome is an autoimmune disease that primarily affects two organs - the lungs
and the kidneys.
It causes inflammation and eventually bleeding in the lungs which leads to 'hemoptysis'
or coughing up of blood, and hematuria or blood in the urine, a pattern first recognized
by the pathologist - Dr. Ernest Goodpasture.
To understand Goodpasture syndrome, let's start by thinking about the basement membrane
which is a thin, sheet-like layer of tissue made of protein that keeps the epithelium
stuck firmly to actual organ - a bit like double-sided tape which keeps gift wrapping
paper stuck to the gift.
The basement membrane is made up of various proteins, but the major one is collagen, and
since basement membrane exists throughout every organ system, it's no wonder that
collagen is the most abundant protein in the human body.
As far as proteins go, collagen is a pretty awesome looking one, with a triple-helix structure
composed of three separate chains that are intertwined like braided hair.
Each of the chains can be one of six types, named α1 through α6, and the most common
form of collagen found in the basement membrane is collagen type IV, which is made by mixing
and matching these six α-chains.
One version of type IV collagen combines the α3, α4, and α5 chains.
Another combines two α1's and an α2.
A third version has two α5's and an α6.
And so on.
So it turns out that the α3/α4/α5 variant is most common in the glomerular basement
membrane of the kidneys and the alveolar basement membrane of the lungs.
In Goodpasture syndrome, autoantibodies bind to a specific part of the α3 chain that is
usually hidden deep within the folded chains.
This is an example of a type II hypersensitivity reaction, because once these autoantibodies,
usually IgG but rarely IgM or IgA, bind to the the α3 chain, they activate the complement
system.
The complement system is a series of small proteins present in the blood that act like
an enzymatic cascade to fight off bacterial and other pathogenic invasions.
When the Fab portion of the IgG molecule inappropriately binds to the α3 chain, C1, the first of the
complement proteins, binds to the Fc portion of the IgG.
This bound C1 is now activated and it starts engaging other members of the complement family,
C2 through C9.
Some of these are activated by being cleaved or chopped by an enzyme.
The cleaved fragments C3a, C4a, and C5a act as chemotactic agents meaning they attract
certain cells like neutrophils.
Once neutrophils join the party, they dump a bunch of enzymes like peroxidase, myeloperoxidase,
and proteinase-3 which all cause free oxygen radicals to form which damage the basement
membrane as well as the nearby endothelium and the underlying organ itself.
Genetic risk factors for Goodpasture syndrome include having genes that encode a specific
type of immune molecule called HLA-DR15 which is used to identify and bind to foreign molecules.
Environmental risk factors also play a role, and it relates back to the fact that the autoantibodies
bind to a specific part of the α3 chain that is usually hidden deep within the folded chains.
When the collagen molecules are damaged by infection, smoking, oxidative stress, or some
hydrocarbon-based solvents as in the case of people who work in the dry-cleaning industry,
these antigenic regions on the α3 chain get exposed to the antibodies present in the blood
of genetically susceptible people.
This also helps explain why Goodpasture syndrome specifically affects the kidney and the lungs.
The kidney filters toxins from the blood, so as they pass through the basement membrane
of the kidney they likely expose parts of the α3 chain and similarly, the lungs get
exposed to various inhaled toxic substances - like cigarette smoke - once again, exposing
the parts of the α3 chain that lead to Goodpasture syndrome.
In Goodpasture syndrome, lung symptoms usually come before kidney symptoms.
Damage to the basement membrane in the lungs causes widespread damage to the alveoli, the
small air-sacs where the gas exchange occurs between the air we breathe in and the blood,
leading to a cough and hemoptysis or blood in the sputum.
The damage to the alveoli can also impair the ability of the lungs to exchange oxygen
for carbon dioxide leading to a pattern of restrictive lung disease.
Damage to the basement membrane in the kidney affects its ability to filter properly, allowing
blood to get into the urine - hematuria, and protein to get into the urine - proteinuria.
This fits the nephritic syndrome pattern.
The best way to diagnose Goodpasture syndrome is by doing a biopsy, usually of the kidney
because that's the best-studied organ in this disease.
Under a microscope, you usually see , inflammation of the basement membrane, and if fluorescent
proteins that bind to the anti-basement membrane antibodies are used, they light up in a linear
pattern along the basement membrane.
In the past, Goodpasture syndrome was usually fatal, but aggressive treatment with corticosteroids
and immunosuppressive agents as well as plasmapheresis, which involves filtering out the fluid part
of blood or plasma, has improved the prognosis with fewer individuals developing chronic
renal failure and needing dialysis.
Alright, let's recap - Goodpasture syndrome is an autoimmune disease in which the immune
system attacks the α3 chain of Type IV collagen present in basement membrane.
The specific spot that gets affected is usually well hidden but gets exposed by various toxins,
which is why the disease predominantly affects the lungs and kidneys causing symptoms like
hemoptysis and hematuria.
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