How Benacerraf and McDevitt Redefined Autoimmune Disease
Marking the 50th anniversary of a seminal paper in rheumatology
Fifty years ago, a scientific breakthrough fundamentally changed how we understand autoimmune diseases like rheumatoid arthritis, lupus, and ankylosing spondylitis. In 1972, immunologists Baruj Benacerraf and Hugh McDevitt published a seminal paper in Science that introduced the concept of histocompatibility-linked immune response genes 1 . Their work established that our genetic makeup—specifically genes within the major histocompatibility complex (MHC)—plays a crucial role in determining how our immune system responds to threats, and perhaps more importantly, how it sometimes mistakenly targets our own body.
This discovery not only earned Benacerraf a share of the Nobel Prize in Physiology or Medicine in 1980 (an honor many believe McDevitt should have shared) but also created a foundation upon which decades of rheumatology research have been built . As we mark the anniversary of their groundbreaking work, we explore both their enduring legacy and the emerging questions that continue to challenge scientists today.
1920-2011
Medical College of Virginia
Nobel Prize in Physiology or Medicine 1980
1930-2022
Harvard Medical School
National Medal of Science 2000
Though they collaborated on one of immunology's most important papers, Benacerraf and McDevitt came from strikingly different backgrounds—a testament to how diverse perspectives can drive science forward.
Born in Caracas to Sephardic Jewish parents who had immigrated from North Africa. His family moved to Paris when he was five but returned to Venezuela in 1939 just in time to escape the Nazi occupation of France. Despite his father's hopes that he would join the family business, Benacerraf pursued medicine with unwavering determination. He faced significant adversity, later recounting that he was accepted to only one medical school (the Medical College of Virginia), which he attributed to the discrimination against Jewish students prevalent at the time .
Grew up in Wyoming, Ohio, just outside Cincinnati. His story could not have been more different. His father, a general surgeon, began taking him on hospital rounds as early as third grade—partly to inspire him toward medicine and partly to avoid Sunday church services. These early exposures to medicine, complemented by chocolates from sympathetic nurses, sparked a lifelong passion for medical research. McDevitt's father often shared stories about Paul Ehrlich, whose "side chain theory" of cellular receptors foreshadowed McDevitt's own work on antigen presentation .
Despite their different paths, both men arrived at the same revolutionary idea: that our genes control immune responses.
Before Benacerraf and McDevitt's work, scientists knew that genetic factors influenced disease susceptibility but didn't understand the mechanisms. The major histocompatibility complex (MHC) was primarily studied for its role in organ transplant rejection, not immune regulation.
The breakthrough began with Benacerraf's work with Ira Green and Bill Paul using guinea pigs. They discovered that when exposed to simple synthetic antigens, some animals mounted strong immune responses while others didn't—and this difference was heritable . Meanwhile, McDevitt, working with colleagues like Michael Sela and Len Herzenberg, was making similar discoveries in mice and pinpointing the precise location of these immune response genes within the MHC .
In their seminal 1972 paper, Benacerraf and McDevitt synthesized these findings into a coherent theory: that specific genes within the MHC—which they termed "immune response genes"—controlled whether an individual could mount an immune response to particular antigens 1 . They boldly speculated that these genes might explain why some people developed autoimmune diseases while others didn't.
The critical question driving Benacerraf and McDevitt's research was: Why do individuals respond differently to the same antigen? They hypothesized that genetic factors controlled these differences, and specifically that these factors were located within the major histocompatibility complex.
The experiments demonstrated that the ability to mount an immune response to simple antigens was genetically determined and MHC-linked. Guinea pigs with certain MHC genes produced strong immune responses to specific antigens, while those with different MHC genes did not—even when exposed to identical antigens .
This finding was revolutionary because it established that:
Fifty years later, we can say Benacerraf and McDevitt were both right and not entirely right. Their fundamental insight—that MHC genes influence immune disease susceptibility—has been overwhelmingly validated. However, the exact mechanisms may be different than they originally envisioned .
The strongest validation came just 15 months after their paper, when two independent studies discovered that HLA-B27 dramatically increased susceptibility to ankylosing spondylitis—by some estimates, carrying a 100-200 times greater risk . Since then, numerous other HLA associations have been discovered:
Despite these advances, there remains a dearth of evidence that human MHC molecules directly control immune responses to self-antigens as originally hypothesized . For example:
Emerging research suggests that HLA molecules might influence disease susceptibility primarily through their effect on the microbiome—the collection of bacteria, viruses, and fungi that inhabit our bodies, especially our gut .
Consider these fascinating findings:
This suggests a revised hypothesis: Perhaps HLA molecules don't primarily control responses to self-antigens but instead shape our immune response to commensal bacteria. Depending on which bacteria are present, this might then trigger cross-reactivity with self-antigens or general inflammation that breaks immune tolerance .
| Disease | HLA Marker | Relative Risk | Year Discovered |
|---|---|---|---|
| Ankylosing spondylitis | HLA-B27 | 100-200 | 1973 |
| Rheumatoid arthritis | HLA-DRB1*04 | 4-6 | 1978 |
| Celiac disease | HLA-DQ2.5 | 7-10 | 1987 |
| Type 1 diabetes | HLA-DQ8 | 4-9 | 1987 |
| Psoriatic arthritis | HLA-B27 | 5-10 | 1975 |
| Aspect | Original Hypothesis (1972) | Revised Hypothesis (2022) |
|---|---|---|
| Primary role of MHC | Control response to self-antigens | Shape response to microbiome |
| Key mechanism | Antigen presentation to T cells | Multiple mechanisms including antigen presentation, protein folding, and NK cell activation |
| Environmental factors | Secondary triggers | Essential co-factors |
| Therapeutic implications | Target antigen presentation | Modify microbiome or broader immune responses |
Benacerraf and McDevitt's 1972 paper represents that rare scientific publication that truly rewrites textbooks. Their insight that immune response genes within the MHC control disease susceptibility has inspired generations of researchers and produced thousands of subsequent studies.
"Great science isn't about being permanently right but about asking the right questions that push a field forward. Benacerraf and McDevitt's true legacy isn't just what they discovered but the scientific pathways they opened for others."
The emerging connections between HLA, the microbiome, and autoimmune disease represent the next frontier in this ongoing exploration. Just as Benacerraf and McDevitt built on the work of pioneers like Paul Ehrlich and George Snell, today's researchers stand on the shoulders of these two giants as they work to complete the puzzle of autoimmune disease .
What makes their 1972 paper truly timeless isn't its definitive answers but its powerful question: "How do our genes guide our immune responses?" Fifty years later, we're still pursuing the full answer—and benefiting from the foundation they laid.
References will be added here in the final publication.