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Women caught in a pickle by their own immune systems

June 11, 2019

ASU scientists develop new hypothesis to explain sex differences in human diseases

Women get autoimmune diseases, such as multiple sclerosis, lupus and rheumatoid arthritis, eight times more than men do. On the other hand, women have a smaller risk of getting nonreproductive cancers such as melanoma and colon, kidney and lung cancer.

And while there are some exciting developments in cancer treatments, such as immunotherapies, research is showing that women are responding more favorably than men to this type of intervention. 

So why is there such a big difference between women and men when it comes to human diseases?

An interdisciplinary team of scientists at Arizona State University believes it may have the answer.

In a paper published Tuesday in the scientific journal “Trends in Genetics,” the team presents a new hypothesis to explain the phenomenon, setting the stage for novel research avenues focused specifically on treating autoimmune diseases and cancer.

“Until now, the differences between women and men in regards to human diseases have not been explained by existing theories,” said Melissa Wilson, assistant professor with ASU’s School of Life Sciences and senior author of the paper. “We are proposing a new theory called the Pregnancy Compensation Hypothesis. 

pregnancy hypothesis

An illustration of the expected immune differences between high and low parity (layered on top of high/low pathogen load). The study suggests that low pathogen load (hygiene hypothesis) affects immune function in both men and women (green lines), making everyone more susceptible to autoimmune disease, whereas low parity will only affect the immune system in women, exacerbating the immune compensation that evolved in response to tolerating an internal pregnancy, further increasing the immune risk for women in industrialized regions.

“Basically, women’s immune systems evolved to facilitate their survival during the presence of an immunologically invasive placenta and pregnancy, and compensate so they could also survive the assault of parasites and pathogens. But now, in a modern, industrialized society, women are not pregnant all the time so they don’t have a placenta pushing back against the immune system. The changes in their reproductive ecology exacerbate the increased risk of autoimmune disease because immune surveillance is heightened. At the same time, we see a reduction in some diseases, like cancer,” Wilson said.

Heini Natri, the lead author of the study and a postdoctoral scholar with the ASU Center for Evolution and Medicine, said because the immune system varies between the sexes, it should be considered when developing immunotherapies and other treatments. 

“We think the Pregnancy Compensation Hypothesis can explain why there’s a big sex difference in these diseases. Going forward, understanding the evolutionary origin of the sex bias in these diseases can help us better understand the mechanisms and particular pieces of the immune system we can target,” Natri said. “Our goal is to actually make treatments better for everyone. We are realizing that cancer is different in men and women. In the study of most cancers and other diseases, and so far in the development of cancer treatments, that has not really been taken into account.”

Effects of industrialization

Another factor that may exacerbate this situation is living a modern-day, urban lifestyle.

In industrialized communities, autoimmune diseases appear to occur at a much higher rate than in nonindustrialized populations. The researchers believe the human immune system evolved expecting a given load of parasites. In the modern environment, exposure to those parasites has diminished so the immune system has fewer foreign targets. With this reduced load, the immune system attacks 'self' but also finds cancer.

“There is a mismatch between the ancestral environment humans were adapted to, and the industrialized environment many people currently live in. In terms of an evolutionary timescale, our environment has changed incredibly fast,” said Angela Garcia, also a postdoctoral research fellow with the center. 

“We have also shifted from an active lifestyle to a sedentary one. We now have an overabundance of calories available, which potentially allows us to maintain excessive levels of hormones, including the female hormone estradiol. Maintaining such high levels of hormones may increase the chance of triggering autoimmune diseases,” she said.

graphic on sex differences

Although evolution has shaped sex differences over millions of years, industrialized urban populations experience exacerbated sex differences in hormone mechanisms as well as reduced pregnancies compared with nonindustrialized populations.

Future treatments  

The researchers suggest that by framing future research within the Pregnancy Compensation Hypothesis, scientists could dive deeper into the characterization of genes, environmental context and the longitudinal history of people. 

“We think this is more than a hypothesis. By using modern molecular biologic techniques in genetics and genomics, we can look at the differences between male and female immune systems, and between modern immune profiles and those in pre-industrial populations. By doing so, we may find new ways to prevent cancer and autoimmune diseases,” said Ken Buetow, a professor with the school and co-author of the study.

The researchers also suggest there are places where genes are regulated uniquely in males and females, as well as across environmental contexts.

“Going forward, we need to systematically collect environmental variables like pathogenic exposure, levels of stress and reproductive hormones and parity. We have to understand these areas better,” Wilson said. 

sexual differences in disease diagram

This study is an interdisciplinary, collaborative effort including researchers from the School of Life Sciences, Center for Evolution and Medicine, and the School of Human Evolution and Social Change. This study is supported by the following: ASU School of Life Sciences; ASU Center for Evolution and Medicine; Prevent Cancer Foundation; Marcia and Frank Carlucci Charitable Foundation; ASU Biodesign Institute; National Institute of General Medical Sciences of the National Institutes of Health #R35GM124827; National Institute on Aging #RF1AG054442-01.

Top illustration: Jacob Sahertian/ASU VisLab

Sandra Leander

Assistant Director of Media Relations , ASU Knowledge Enterprise


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New business tool demonstrates responsibility toward society

June 11, 2019

ASU professor says firms are embracing social accounting as a business strategy

In its May newsletter, Salt River Project gave tips to consumers on how to save money using its new pricing plans and what to do in case of an outage. They also listed where they gave more than $3.6 million in donations to 358 different organizations last year.

Businesses, companies and large organizations like SRP are investing in a larger responsibility toward society by putting their money — and kind deeds — where their mouths are.

Ten years ago, examples of such corporate social responsibility would merely be publicity. Now, however, a fairly new concept called “social accounting” helps firms explain how generosity relates to their business strategy. It builds consumer trust, increasing investor confidence in its decision-making and business model.  

Social accounting accomplishes that goal by communicating how a firm’s operations create value for the organization and the community. This increases organizational transparency, strengthens stakeholder trust and provides an indicator of future performance.

Arizona State University’s Elizabeth Castillo, an assistant professor in organizational leadership with the College of Integrative Sciences and Arts, spent 20 years in management and is an expert on social accounting.

Castillo spoke to ASU Now about this new business tool, which is taking hold around the globe.

Woman in glasses with pendant

Elizabeth Castillo 

Question: What is your definition of social accounting?

Answer: Social accounting is a business tool to track and report a company’s performance along multiple dimensions — financial, environmental and social. Besides financial statements, it includes qualitative analysis and quantitative measures for assets like human resources, such as employee satisfaction, diversity, training and development; environmental impacts such as carbon emissions and water consumption; and intangibles such as intellectual capital, reputation and governance.

Tracking all these dimensions in an integrated way enables a firm to understand and evaluate its decision-making systematically and to show how its choices impact employees, investors, suppliers, regulators and the community. In sum, social accounting is a holistic way for the firm to strategize and communicate how it creates value for its stakeholders and society.

Q: When and how did this movement gain traction?

A: Businesses have long recognized they must hold themselves accountable to the community to remain viable. In previous centuries, this was easy to do because consumers, investors and businesses were geographically proximate. As business became more global and complex, more sophisticated methods for accountability were needed and developed, primarily financial accounting and auditing. However, in the last half of the 20th century, the negative impacts of this purely financial focus became more visible. Through media coverage, the public became aware of harmful systemic practices like environmental destruction and racial discrimination. Social audits emerged in the 1970s as a way to publicize and remedy these practices. In the 1980s, social audits began to be standardized so results could be compared. In the 1990s, business started to use social audit data to improve their operating performance. This led to frameworks and concepts such as the Balanced Scorecard, triple bottom lineThe triple bottom line looks at benefits to people, profit and planet. and corporate social responsibility reporting.

In the last decade, social accounting has become increasingly sophisticated. Standards-based models include the Global Reporting Initiative and the Sustainability Accounting Standards Board framework. Principles-based models include integrated reporting which tracks six types of resource inputs — human, natural, financial, manufactured, relational and intellectual — and depicts how a firm transforms those into outputs, outcomes and societal impact. Dr. Laurie Mook and Dr. Sandra Cherie Henderson are doing important work on similar social accounting models.

Q: What are the benefits and value added to companies who incorporate this practice?

A: Social accounting, particularly integrated reporting (IR), provides benefits at multiple levels. It gives organizations information to understand how their resource allocation decisions produce organizational success and profitability. This detailed, relational understanding enables them to devote attention to what matters most to their long-term performance. IR’s focus on capitalsResources that endure and can produce more resources. also conveys future value creation potential, providing helpful insights for investors. Finally, IR improves internal management and decision making by fostering holistic understanding of the firm’s operations and its interdependencies with stakeholders and the environment. This strengthens accountability and illuminates the company’s positive and negative impacts on society, or externalities.

At the societal level, integrated reporting promotes transparency, trust and legitimacy in the eyes of the public. It also gives investors information they need to more accurately assess future prospects for profitability and sustainability. For example, some companies report on the number of their internal ethics investigations. This gives investors a more accurate picture of risk exposure. Perhaps most importantly, social accounting connects organizational actions to community and planetary indicators such as the U.N.’s Sustainable Development Goals. By illuminating intangible resources like relationships, knowledge, ecosystem services, and trust, integrated reporting makes the foundations of sustainable commerce visible and actionable. It also makes businesses accountable. For all these reasons, IR is widely regarded as an enabler of financial stability for firms and the entire economy.

Q: The cynic in me says it sounds like a lot of extra work and is labor intensive.

A: That’s a common concern, yet people who use integrated reporting say the amount of work is not burdensome. For example, two researchers developed an integrated report for Exxon in about 40 hours. Thus, time and information availability are not barriers. The hard part — at least initially — is changing a company’s mindset about what it means to manage. Rather than the conventional approach where departments act in silos, IR calls for holistic understanding of the firm, internally across departments and externally by recognizing interdependencies with stakeholders and the operating environment.

As firms become familiar with the IR process, they report enhanced capacity for integrative thinking and better comprehension of their value creation ecosystem. For example, 2014 research by BlackSun and the International Integrated Reporting Council found that 96% of responding firms experienced increased cross-departmental collaboration, respect and communication when they used IR. Other benefits included broadening perspectives, enhancing shared understanding of their company’s value creation process and improving their decision-making. This integrative understanding is also beneficial to new organizational forms such as B Corps and social enterprises, and government agencies and nonprofit organizations.

Q: Which countries are leading the way in this practice, and which companies in the United States are successfully incorporating social accounting?

A: South Africa is the world leader in social accounting. This is because integrated reporting is required there for firms listed on its stock exchange. Japanese companies are rapidly adopting IR because their government recently encouraged its use. Integrated reporting is also gaining traction in the United Kingdom, where it has been adopted by the Crown Estate.

The big four accounting firms have all published papers and guidance on integrated reporting, including Deloitte, Ernst Young, KPMG and PwC. The International Integrated Reporting Council’s U.S. Community has presented webinars on American companies that have adopted IR. You can watch these videos to get a better understanding of these organizations’ experiences, including Clorox, Etsy, Coca-Cola, Intel and the American Institute of CPAs (AICPA). For companies interested in learning more about Integrated Reporting, the IIRC has a library of “how-to” guides and a database of exemplar reports sharing best practices.

Top photo: Photo illustration courtesy of Getty Images/iStock. 

Reporter , ASU News