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Goodpasture's Syndrome

Kelly Carter
Davidson College
BIO 307, Immunology
Dr. A. Malcolm Campbell

What are the symptoms of Goodpasture's Syndrome?
Normal Renal Anatomy
Progress of Goodpasture's Syndrome
        Basement Membrane Damage
        Production of Anti-GBM Antibodies
        Tissue Damage
Diagnosis of Goodpasture's Syndrome
Treatment of Goodpasture's Syndrome
Works Cited
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What are the symptoms of Goodpasture's Syndrome?
        Patients with Goodpasture's Syndrome (referred to from here as GS) usually present with pulmonary hemorrhage, evidenced by hemoptysis (coughing up blood), and glomerulonephritis, evidenced by hematuria (blood in the urine) (Avella et al., 1999).  While more than 50% of GS cases present with pulmonary hemmorhage, some patients also present with no renal symptoms (Avella et al., 1999; Kuzmanic  et al., 1999).  These patients may be mid-way through the course of GS, as pulmonary hemorrhage may precede renal symptoms by weeks or months (Avella et al., 1999).  The lung pathology of a patient who died of GS is shown below.  Note the extensive necrosis (black areas as opposed to the pink area in the upper left quandrant):

Lung pathology of Goodpasture's Syndrome.  Used with permission of author.  Source:

Normal Renal Anatomy

    Before we discuss the disease pathology, it would be useful to review normal renal pathology.  GS involves the basement membranes, which form a barrier whenever cells (specifically in organs) meet connective tissue (Hellmark et al., 1996).  The basement membrane has a stable skeleton of Type IV collagen, onto which other basement membrane molecules, such as proteoglycans, attach (Hellmark et al., 1996). Spaces in the basement membrane enable filtration of large amounts of water and small solutes, but electrostatic interactions with proteoglycans prevent filtration of plasma proteins from the blood (Guyton et al., 1996).  Below is a schematic image of a normal glomerulus.  Note the position of the basement membrane.


Normal Glomerular Capillary. Used with permission of author.  Source:

       Each strand of Type IV collagen is composed of three subunits, or a (IV) chains (Hellmark et al., 1996).  These a chains may be grouped into six genetically distinct categories, with a1 and a3 being of particular interest when studying GS (Hellmark et al., 1996).  The basement membranes of the glomeruli and alveoli share a unique combination of a1 and a3 Type IV collagen (Hellmark et al., 1996).

Progress of Goodpasture's Syndrome

Basement Membrane Injury
        Goodpasture's Syndrome begins with injury to the basement membrane that exposes the Type IV collagen backbone (Kalluri, 1999).  Proposed routes of basement membrane injury include smoking, inhalation of volatile hydrocarbons or other toxins, renal injury, incidental glomerulnephritis or ischemia (Kalluri, 1999; Avella et al., 1999).

Production of Anti-GBM Antibodies
        After exposure of the collagen in the basement membrane, the body intiates an autoimmume reaction to the a3 chain of the Type IV collagen.  These antibodies against a3 chain of the Type IV collagen are also called anti-Glomerular Basement Membrane (GBM) Antibodies or Goodpasture's antibodies.  The inappropriate immune response may be enabled by deficiency in an Fc receptor.
        Fc receptors bind to the Fc portion of immunoglobulin (Ig) molecules (Janeway et al., 1999).  The specificity of the receptor is based on recognition of the alpha domain on the Fc molecule (Janeway et al., 1999).  FcgR-IIB is one type of Fc receptor that is expressed on macrophages, neutrophils, eosinophils, B cells and mast cells (Janeway et al., 1999).  FcgR-IIB expression on B cells may prevent activation of low-affinity autoreactive cells during affinity maturation and may also prevent the development of autoreactive memory cells in the germinal centers (Nakamura et al., 2000).  The FcgR-IIB receptor inhibits the response of these autoreactive cells when crosslinked with the B cell receptor (BCR) by binding to SHIP (Nakamura et al., 1999; Janeyway et al., 1999).  The FcgR-IIB receptor may also trigger apoptosis when it crosslinks to itself without BCR (Nakamura et al., 1999).
        Animals deficient for FcgR-IIB have stronger immune responses and more inflammation in all antibody-mediated types of hypersensitivity reactions than animals with normal expression of the receptor (Nakamura et al., 1999).  When the FcgR-IIB mice are immunized with Type IV collagen, they develop an autoimmune disorder similar to GPS:  pulmonary hemorrhage and nephritis consistent histologically with the pathology of GPS (Nakamura et al., 1999).  This tissue damage did not occur systemically, supporting the idea that the pathology was not the result of generalized inflammation (Nakamura et al., 1999).  The tissue damage associated with GPS is thought to be caused by the anti-GBM antibodies binding to the a3 chain of the Type IV collagen in the basement membrane of the glomeruli and alveoli (Nakamura et al., 1999).  These antibodies bind and activate effector cell responses (Nakamura et al., 1999).

Tissue Damage
        The recruitment of effector cells and the subsequent inflammatory response decreases the blood flow to the glomerulus (Avella et al., 1999).  This stimulates formation of crescents in the glomerulus, as seen below (Kaplan, 1997).
* compare with first schematic image of a normal glomerulus, with the open lumen.

Crescent formation in glomerulonephritis associated with Goodpasture's Syndrome.  Used with permission of authors.  Source:

        Another mechanism for Goodpasture's syndrome is that susceptible MHC-II alleles may bind selectively to a3 chain of the Type IV collagen, prompting T cell recognition of these fragments (Kalluri, 1999).  Goodpasture's syndrome has been correlated with HLA DR2 and DR4 alleles (Levy et al., 1996).
        Goodpasture's syndrome is a unique autoimmune reaction in that it is monophaic:  it occurs only once (Levy et al., 1996).  Recurrence of clinical symptoms or anti-GBM antibodies is very rare;  only ten cases of recurrence have been reported (Levy et al., 1996).  This may be because the antigen (a3 chain of the Type IV collagen) is usually "hidden" in the intact basement membrane (Levy et al., 1996).  Since the body is not continuously exposed to the antigen, it may recover from the initial autoimmune reaction (Levy et al., 1996).  This is not to say that most people recover from Goodpasture's Syndrome with no medical intervention, only that those who do receive medical support will usually not have a recurrence of the syndrome.

How is Goodpasture's Syndrome Diagnosed?
    When a patient presents with the initial indicators of Goodpasture's Syndrome (hemoptysis and hematuria), an anti-GBM antibody titer, bronchoscopy and renal biopsy may provide a definitive diagnosis of GS (Avella et al., 1999).  The anti-GBM antibody titer is indicated when patients have acute renal failure, pulmonary hemorrhage and/or rising serum creatine concentrations with hematuria (Hellmark et al., 1997).  The Anti-GBM antibody titer may eliminate other disorders, as these symptoms may be indicative of other diseases (Hellmark et al., 1997).  A definitive diagnosis of GS will include an anti-GBM Ab titer test of greater than 20 units (normal = 0-9 units), bloody secretions in the bronchoscopy, and a linear distribution of IgG on the basement membrane of the renal biopsy (Avella et al., 1999).  An example of the linear distribution of IgG on the glomerular basement membrane is shown below:


Immunoflorescence image of linear distribution of IgG on glomerular basement membrane  Used with permission of author. Source:

Treatment of Goodpasture's Syndrome
The traditional course of treatment for GS has been pulse-dose of steroids (methyl prednisone), followed by oral steroids and immunosuppressants (cyclophosphamide), with initiation of plasmapheresis at the diagnosis of GS (Hellmark et al., 1997).  The immunosuppressants inhibit synthesis of new anti-GBM antibodies, while the plasmapheresis removes existing anti-GBM antibodies and complement factors from the blood (Harada et al., 1998; Kaplan, 1997).  In a comparison of GS patients who received immunosuppressants alone versus patients receiving immunosuppressants and plasmapheresis, the dual-treatment group experienced a faster decline in anti-GBM antibodies and had half the serum creatine level of the single treatment group (Harada et al., 1998).  The efficacy of plasmapheresis has been disputed, though, and one clinician noted that early diagnosis and initiation of treatment is the best indicator of positive renal outcome (Kaplan, 1997).

Works Cited

Avella, P et al.  Goodpasture's Syndrome:  A Nursing Challenge.  Dimensions in Critical Care Nursing.  18(2):  2-11.  Mar-Apr 1999.

Guyton, A et al.  Textbook of Medical Physiology.  9th ed.  Philadelphia, PA:  WB Saunders Company.  1996.

Harada, T et al.  Therapeutic Apheresis for Renal Diseases.  Therapeutic Apheresis.  2(3):  193-98.  1998.

Hellmark, T et al.  Anti-GBM Antibodies in Goodpasture Syndrome;  anatomy of an epitope.  Nephrology, Dialysis and Transplant.  12:  646-48.  1997.

Janeway, C et al.  Immunobiology:  The Immune System in Health and Disease.  4th ed.  New York:  Garland Publishing.  1999.

Kalluri, R.  Goodpasture's Syndrome.  Kidney International.  55: 1120-22.  1999.

Kaplan, A.  Therapeutic Plasma Exchange for the Treatment of Rapidly Progressive Glomerulonephritis.  Therapeutic Apheresis.  1(3):  255-59.  1997.

Kuzmanic, D et al.  Goodpasture's Syndrome with Normal Renal Function.  Clinical Nephrology.  51(5):  319-20.  May 1999.

Levy J et al.  Recurrent Goodpasture's Disease. American Journal of Kidney Diseases.  27(4):  573-78.  April 1996.

Nakamura A et al.  Fc gamma Receptor IIB-deficient Mice Develop Goodpasture's Syndrome upon Immunization with Type IV Collagen:  A Novel Murine Model for Autoimmune Glomerular Basement Membrane Disease.  Journal of Experimental Medicine.  191(5):  899-905.  March 6, 2000.

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